Context  The effect of global health initiatives on population health is uncertain. Between 2003 and 2008, the US President's Emergency Plan for AIDS Relief (PEPFAR), the largest initiative ever devoted to a single disease, operated intensively in 12 African focus countries. The initiative's effect on all-cause adult mortality is unknown.

Objective  To determine whether PEPFAR was associated with relative changes in adult mortality in the countries and districts where it operated most intensively.

Design, Setting, and Participants  Using person-level data from the Demographic and Health Surveys, we conducted cross-country and within-country analyses of adult mortality (annual probability of death per 1000 adults between 15 and 59 years old) and PEPFAR's activities. Across countries, we compared adult mortality in 9 African focus countries (Ethiopia, Kenya, Mozambique, Namibia, Nigeria, Rwanda, Tanzania, Uganda, and Zambia) with 18 African nonfocus countries from 1998 to 2008. We performed subnational analyses using information on PEPFAR's programmatic intensity in Tanzania and Rwanda. We employed difference-in-difference analyses with fixed effects for countries and years as well as personal and time-varying area characteristics.

Main Outcome Measure  Adult all-cause mortality.

Results  We analyzed information on 1 538 612 adults, including 60 303 deaths, from 41 surveys in 27 countries, 9 of them focus countries. In 2003, age-adjusted adult mortality was 8.3 per 1000 adults in the focus countries (95% CI, 8.0-8.6) and 8.5 per 1000 adults (95% CI, 8.3-8.7) in the nonfocus countries. In 2008, mortality was 4.1 per 1000 (95% CI, 3.6-4.6) in the focus countries and 6.9 per 1000 (95% CI, 6.3-7.5) in the nonfocus countries. The adjusted odds ratio of mortality among adults living in focus countries compared with nonfocus countries between 2004 and 2008 was 0.84 (95% CI, 0.72-0.99; P = .03). Within Tanzania and Rwanda, the adjusted odds ratio of mortality for adults living in districts where PEPFAR operated more intensively was 0.83 (95% CI, 0.72-0.97; P = .02) and 0.75 (95% CI, 0.56-0.99; P = .04), respectively, compared with districts where it operated less intensively.

Conclusions  Between 2004 and 2008, all-cause adult mortality declined more in PEPFAR focus countries relative to nonfocus countries. It was not possible to determine whether PEPFAR was associated with mortality effects separate from reductions in HIV-specific deaths.