The livers of 21 rhesus monkeys inoculated with SIVmac251 were examined at 4 days to 39 months after infection. SIV antigens were detected in the cytoplasm of Kupffer cells (KC), macrophages and lymphocytes in two-thirds of the livers tested. The number of cells containing viral proteins substantially increased during the development of the disease, and KC were the main cell type displaying SIV proteins at an advanced stage of infection. Mature and immature lentiviral particles were found in cytoplasmic vacuoles or associated with worm-like structures in KC, indicating that SIV replication could occur within resident liver macrophages. Another sign of the permissiveness of KC was the formation of multinucleated giant cells within the hepatic sinusoids. Some of these cells containing 3-6 nuclei still retained ultrastructural features of KC. Most of them contained a high quantity of viral particles. Numerous lymphocytes displaying signs of apoptosis were taken up by KC, especially at the beginning of infection. Hyperplasia and hypertrophy of KC were noted in the course of SIV disease in the liver. The present data indicate that KC can be infected in vivo and may serve as a reservoir for SIV during the progression of the disease.