$3 trillion. That's a staggering figure. And it's roughly how much is spent on healthcare each year in the U.S. alone. With that much money changing hands, there are plenty of companies making lots of profit. But which are the most profitable?

The best metric to use in answering this question is profit margin -- the amount of profit made as a percent of revenue. Below are the 10 most profitable healthcare companies based on profit margin with market caps of at least $200 million. 

Company Profit Margin
AMAG Pharmaceuticals (AMAG) 109.19%
PDL BioPharma (PDLI) 66.11%
Enanta Pharmaceuticals (ENTA 7.59%) 65.80%
NewLink Genetics Corporation (NLNK) 59.60%
Shire plc (NASDAQ: SHPG) 56.55%
Taro Pharmaceutical Industries Ltd. (NYSE: TARO)  52.31%
ANI Pharmaceuticals (ANIP 1.69%) 51.36%
Gilead Sciences (GILD 1.06%) 48.62%
Vanda Pharmaceuticals (VNDA 2.77%) 40.25%

Birds of a feather?
Several of the 10 most profitable healthcare companies have things in common. For example, seven of the companies listed are biotechs. The three exceptions to this -- AMAG, POZEN and Taro -- are pharmaceutical companies that don't fit under the biotech umbrella. Healthcare includes hospitals, medical device makers, software companies, insurers, and others, but none of them made the top 10 for profitability.

When it comes to profitability, it appears that small is big. Seven on the list have market caps well below the $3 billion, qualifying them as small cap stocks. Taro's market cap is the least of the three outliers at a little over $6 billion. Shire's market cap stands at nearly $48 billion. Meanwhile, Gilead Sciences is worth more than all other nine companies combined -- with a market cap topping $157 billion.

Source: Gilead Sciences

There's another perhaps counter-intuitive similarity among most of the top 10: relatively low valuation. Only one company on the list carries a trailing 12-month earnings multiple that is higher than that of the S&P 500 index -- ANI Pharmaceuticals, which has a P/E of 24. Eight of the companies claim earnings multiples below 15.

Of course, investors often look more closely at valuation levels based on future earnings estimates. Several of the most profitable healthcare companies look relatively inexpensive on that front, also. Three have current share prices that are less than 10 times their forward earnings estimates: AMAG, Gilead and PDL BioPharma. Meanwhile, Enanta, POZEN and Taro all have forward P/E ratios below 15.

Profitable picks?
Which of these highly profitable companies could also be the most profitable picks for investors? That's a tough question, because those disclaimers that every financial manager makes about "past performance may not be indicative of future results" can also apply to individual stocks.

PDL BioPharma, for example, makes its money primarily through royalties from drugs that it has licensed to other companies. 71% of its revenue in 2014 came from drugs licensed to Genentech. However, that revenue dries up after the first quarter of 2016. While PDL is working hard to forge deals to make up the gap, there is considerable risk that the company won't be as profitable in the future.

I also suspect that AMAG Pharmaceuticals could be in for some challenges. Nearly 70% of its 2014 sales stemmed from iron-replacement drug Feraheme. In January, though, Rockwell Medical gained FDA approval for Triferic -- an iron-replacement drug that isn't delivered intravenously. Triferic could be a game-changer in ways that make winning more difficult for AMAG.

Source: Taro Pharmaceuticals 

Several of these companies do appear to have a good shot at continued success, though. My top pick is Gilead Sciences. Gilead has several things going for it. The biotech's hepatitis C drugs are raking in billions while providing a cure for the disease for many. Gilead also dominates the HIV drug market. The company has several up-and-coming drugs in other indications, too. And having a cash stockpile of more than $14 billion to reward shareholders through share buybacks and dividend payouts plus invest in new drugs is a huge plus.

Taro Pharmaceuticals is another one that investors might want to check out. The Israel-based company makes most of its revenue from generic drugs, especially in topical creams, ointments, and gels. Taro has seen steady revenue and earnings increases for the last several years. With lots of merger and acquisition activity among generic drugmakers recently, the company could find itself a buyout target down the road.