Because twins share an in utero environment and genetic relationships, similarities and differences between them can provide insight into the epidemiology and natural history of infectious agents, especially human immunodeficiency virus type 1 (HIV-1). Three projects were summarized: HIV-1 transmission and AIDS-free survival in The International Registry of HIV-Exposed Twins; cloning and sequencing of HIV-1 proviral sequences in two sets of identical twins; and transmission and natural history of ovine lentivirus (OvLV) in twin lambs. Both HIV-1 and OvLV transmission were increased for first-born twins. With HIV-1, progression to AIDS appeared independent of zygosity. Development of pneumonitis with experimental OvLV infection was highly concordant in monozygotic lambs. Finally, the identical infected twins in one set had intermingling of each infant's HIV-1 quasispecies, whereas in the second set each twin had its own distinct cluster of quasispecies around a maternal sequence. The studies indicate that most transmission occurs during labor or delivery, and they suggest that immunogenetics may not affect susceptibility to different HIV-1 quasispecies but may affect the manifestations of specific opportunistic diseases.