Peripheral blood lymphocytes obtained from HTLV-II-infected persons (n=13) and cultured in the absence of exogenous stimulator demonstrated augmented spontaneous proliferation (17, 672±5, 498cpm) when compared with cells from healthy donors (1, 921±1, 306cpm). Removal of non-T population did not abrogate the proliferative response of patients' PBMC, suggesting that the proliferation is not related to the autologous mixed lymphocyte reaction. Addition of recombinant inter-leukin-2 (rIL-2; 0.1U/ml) to spontaneously proliferating cultures from HTLV-II-infected persons resulted in a 3-to 4-fold increase in proliferation (61, 985±16, 003); in contrast, PBMC from controls demonstrated 38- to 42-fold increase in their proliferative capacity in response to rIL-2 (77, 256±13, 044). Antibodies to both IL-2 receptor and HLA-DR were able to inhibit the spontaneous proliferation of PBMC from HTLV-II-infected persons in a dose-dependent manner. Furthermore, addition of cyclosporin A, which preferentially blocks accumulation of IL-2 mRNA, also inhibited spontaneous proliferation in a dose-dependent manner. These observations suggest that the spontaneous proliferation of HTLV-II-infected PBMC is at least in part an HLA-DR-driven, IL-2-dependent event, which is not analogous to the AMLR.