The monocytoid tumor cell line U-937 and five derived subclones were infected with the HTLV-IIIB isolate of the human immunodeficiency virus (HIV). Susceptibility to infection and sensitivity to the cytopathic effects correlated with the expression of the T4 antigen on the cell surface. On the basis of these characteristics the lines could be divided into three groups. Less than 10% T4 positive cells were present in the parental line and clone 4; hence productive infection could only be established after a long latency or with a high virus inoculum. These lines showed no or only marginal cytopathic effect. Clone 16 contained more than 95% T4 positive cells and was the most sensitive line to infection with HTLV-IIIB and its cytopathic effect. Cell death was so extensive following infection that no continuous virus producer line could ever be established from clone 16 cells. Cultures with intermediate T4 expression (50-70% T4+ cells) also had intermediate susceptibility to virus infection. Cytopathic changes, even if pronounced, could be overcome in the infected cultures by the addition of uninfected cells and, in each case, a producer line could be established. HTLV-IIIB infection of clone 16 cells could be blocked by preincubation with monoclonal anti-T4 antibodies indicating a close similarity between the HTLV-IIIB receptor on T4 positive T cells and monocytoid cells. The results thus show that T4 positive monocytoid cells can function as target cells for the HIV.