Scientists think that more than twenty years ago truck drivers first spread HIV in Uganda's Rakai District, which lies along a Lake Victoria trade route to the capital city of Kampala. Because commercial sex is widely available along the trade route, HIV quickly spread throughout Uganda and all of Africa. At one time, Uganda had the world's highest HIV infection rates. By the early 2000s it was one of only two developing nations (Thailand is the other) where there was nationwide evidence of declining HIV rates in response to strong prevention programs. UNAIDS indicates in AIDS Epidemic Update that these programs helped reduce the prevalence of HIV infection by more than one-third, from 13% in 1994 to 6.7% in 2005.

Uganda was the first African country to respond powerfully to its HIV/AIDS epidemic. The government began by gathering religious and traditional leaders, along with representatives of other sectors of society, in an effort to reach agreement that the problem had to be confronted. Prevention efforts targeted specific populations or communities. For example, prevention programs that focused on delaying sex and safe sex practices were presented in schools. Community groups were formed to counsel and support those living with the virus. Condom use was heavily promoted.

Unlike Kenya, Uganda began an aggressive campaign against the spread of HIV/AIDS in the mid-1980s, when it had the highest number of recorded HIV cases in Africa. With virtually every family touched by HIV/AIDS, much of the cultural, religious, and psychological stigma has disappeared in Uganda, where HIV infection rates now appear to be declining. Despite a concerted prevention campaign, Uganda's epidemic has not simply steadily declined. Even though education did prompt behavior changes that in turn resulted in lower HIV prevalence among pregnant women in Kampala and other cities from the early 1990s to the early 2000s, the decline was also due in part to increased AIDS mortality.

According to UNAIDS, in AIDS Epidemic Update, data from a 2004 study reveal that HIV infection has increased since 2000 in some rural areas of Uganda, particularly in men and women aged forty to forty-nine. This finding was confirmed in a 2004-05 national HIV household survey, which reported high infection levels among middle-aged Ugandans. The survey discovered irregular condom use (about half the men and women aged fifteen to forty-nine years reported using a condom the last time they had sex with a casual partner) and increasing numbers of men who had sex with more than one sexual partner in the previous year.

Much of the HIV/AIDS epidemic in Kenya and other nations of East Africa has been attributed to the preponderance of wars and political upheaval. It has been commonly assumed that displaced people and refugees are more likely to be HIV infected than people in more stable settings. In AIDS Epidemic Update, the UNAIDS refutes this premise, citing a review of HIV literature on displaced people in eight countries including Uganda that finds no evidence that conflict increases HIV transmission.

There have also been reports of higher than anticipated rates of HIV infection in adults seeking treatment for malaria in Uganda. (Malaria is a serious, infectious disease that is spread by certain mosquitoes. It is most common in tropical climates.) According to UNAIDS, more than 30% of adults treated at district health centers for malaria were also HIV positive. These findings are consistent with reports from other parts of sub-Saharan Africa that malaria is more serious and occurs more frequently in HIV-infected people.

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