The prevalence and titers of antibodies against Kaposi sarcoma-associated herpesvirus (KSHV) in rural Africa are not completely understood, nor are their trends over time in populations in which human immunodeficiency virus (HIV) is also endemic. We examined prevalence, titers, temporal trends, and determinants of anti-KSHV antibodies in each of 3 time periods (1990-1991, 1999-2000, and 2007-2008) within a long-standing, rural population-based cohort in southwestern Uganda. For each period, we measured antibodies to the K8.1 and ORF73 KSHV antigens in approximately 3000 people of all ages (1:1 sex ratio). In all periods, KSHV prevalence increased rapidly through childhood to approximately 90% by age 15 years, plateauing at approximately 95% thereafter. Similarly, antibody titers, particularly against the lytic antigen K8.1, were among the highest seen and increased significantly with age, suggesting sustained viral replication in this population. Male sex was also independently associated with higher prevalence, whereas HIV coinfection was not. A modest reduction in prevalence among children was noted in the most recent period. KSHV seroprevalence and antibodies titers in this rural Ugandan population are the highest yet reported, perhaps reflecting frequent viral reactivation and persistently elevated transmission.