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Background. The simultaneous emergence of human immunodeficiency virus (HIV)-1 group M and HIV-2 into human populations, circa 1921-1940, is attributed to urbanization and changes in sexual behavior. We hypothesized that the initial dissemination of HIV-1, before sexual transmission predominated, was facilitated by the administration, via reusable syringes and needles, of parenteral drugs against tropical diseases. As proxies for highly lethal HIV-1, we investigated risk factors for hepatitis C virus (HCV) and human T cell lymphotropic virus 1 (HTLV-1) infections, blood-borne viruses compatible with prolonged survival, in an area known in 1936-1950 as the most virulent focus of African trypanosomiasis. Methods. Cross-sectional survey of individuals 55 years and older in Mbimou land and Nola, Central African Republic. Dried blood spots were used for HCV and HTLV-1 serologic testing and nucleic acid detection. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were measured by logistic regression. Results. The only risk factor for HCV genotype 4 infection was treatment of trypanosomiasis before 1951 (OR, 3.13; 95% CI, 1.38-7.09). HTLV-1 infection was associated with having received ⩾2 injections of pentamidine for trypanosomiasis chemoprophylaxis (adjusted OR, 2.03; 95% CI, 1.01-4.06) and with transfusions (adjusted OR, 2.82; 95% CI, 1.04-7.67). From historical data, we predicted that 59% of Mbimous 65 years and older would report treatment for trypanosomiasis before 1951; only 11% did so. Conclusions. Treatment of trypanosomiasis before 1951 may have caused iatrogenic HCV transmission. Population- wide half-yearly intramuscular pentamidine for trypanosomiasis chemoprophylaxis in 1947-1953 may have caused iatrogenic HTLV-1 transmission. These and other interventions against tropical diseases could have iatrogenically transmitted SIVcpz, jump-starting the HIV-1 epidemic. The excess mortality among patients with trypanosomiasis treated before 1951 supports this hypothesis. [ABSTRACT FROM AUTHOR]