Spontaneous proliferation of peripheral mononuclear cells is pronounced following measles virus infection at a time when patients mount effective humoral and cell-mediated immune responses and manifest a range of poorly understood immunologic abnormalities. We found spontaneous activity (measles 8000 ± 1200 cpm vs control 1900 ± 350 cpm; P < 0.05) to wax and wane abruptly during the first week after the rash in parallel with expression of the lymphocyte activation marker OKT10. At peak activity, approximately 10% of circulating mononuclear cells were actively synthesizing DNA. Double labeling of individual mononuclear cells with autoradiography and immunoperoxidase demonstrated that B and T lymphocytes as well as monocytes participate in the spontaneous activity. Proliferative activity was increased 3- to 20-fold over control levels in all PBMC subsets such that close to one-third of circulating B cells and monocytes and 5-10% of CD4- and CD8-positive T cells were preparing to divide. Mitogen responsiveness was generally decreased in measles patients (58,800 ± 4600 cpm vs control 97,700 ± 15,500 cpm; P < 0.002). Neither spontaneous proliferation nor mitogen responsiveness was correlated with age, sex, or the presence of complications. Patients with the lowest mitogen responses, however, had the greatest increases in B cell (P < 0.03) and CD8-positive T cell (P < 0.05) proliferation. These data demonstrate that all major immunologic cell types proliferate in response to measles virus infection. Mechanisms by which spontaneous proliferative activity in individual mononuclear subsets could contribute to depressed mitogen responsiveness are discussed. © 1990.