Natural infection of humans with human T-cell lymphotropic virus type I (HTLV-I) and of old world nonhuman primates with the simian counterpart, STLV-I, is associated with development of neoplastic disease in a small percentage of individuals after long latent periods. HTLV-I is also the etiologic agent of a more rapidly progressive neurologic disease, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Macaques have been used experimentally in studies to evaluate HTLV-I candidate vaccines for efficacy, but no evidence of disease was observed. Here we report experimental infection of pig-tailed macaques with STLV-I(sm) and HTLV-I(ACH), both of which were associated with a disease syndrome characterized by rapid onset, hypothermia, lethargy, and death within hours to days. Other pathologic sequelae included diarrhea, rash, bladder dysfunction, weight loss, and, in one animal, arthropathy. Both retroviruses were detected in the central nervous systems of some animals, either by culture or by direct antigen capture for p19 Gag in cerebrospinal fluid. Although virus was recovered throughout infection from peripheral blood mononuclear cells (PBMC), all infected macaques maintained low antiviral antibody titers and stable proviral burdens, which generally ranged between 10 and 100 copies per 106 PBMC. However, of 13 macaques infected with HTLV-I(ACH) or STLV-I(sm), seven animals (54%) died between 35 weeks and 4 1/2 years after infection. This unexpected high mortality within a relatively short time suggests that infection of pig-tailed macaques might be a useful model for studying immune responses to and pathologic events resulting from HTLV-I infection.