To evaluate altitude of birthplace and residence as factors associated with geographic clustering of HTLV-I infection in Colombia, we sampled a total of 670 current residents of the South Pacific coastal lowland and of upland regions (Cali and environs) of the Valle and Cauca Provinces, located at an altitude of 3,100 ft. Among the 255 lowland study subjects, 4.3% had antibody against HTLV-I, compared to 0.9% of the 415 upland study subjects. A hypothesis emerging from this study is that the lower socio-economic status of lowland residents and associated diseases, particularly untreated syphilis and other sexually transmitted diseases, may explain the increased HTLV-I seropositivity rates in this population.