In its first five years, the President's Emergency Plan for AIDS Relief (PEPFAR)--the largest commitment ever by any nation to combat a single disease--succeeded in getting 2.1 million people on antiretroviral treatment and 10.1 million people in care; prevented an estimated 237,600 HIV infections in infants; and saved an estimated 3.28 million adult years of life. Much of the global program's success can be attributed to early decisions to implement new structures and approaches designed to meet its ambitious targets quickly, overcome bureaucratic inertia, and ensure continued progress. A unified US government program was created with a single coordinator. There was a focus on quick ramp-up, strategic partnerships, and sustainable local ownership. Accountability and performance were emphasized. These new approaches played critical roles in translating the unprecedented resources and political support for PEPFAR into improved health for millions of people. Successful aspects of the way in which PEPFAR was organized and implemented, along with less successful or deficient ones, offer lessons for any large, complex international health initiative.