It is not clear whether the accessory function of monocytes from subjects with human immunodeficiency virus (HIV)-related diseases such as acquired immunodeficiency syndrome (AIDS) and persistent generalized lymphadenopathy (PGL) is intact. In this study, the accessory function of monocytes from healthy subjects (n = 9) and subjects with AIDS (n = 4) and PGL (n = 5) was assessed by adding graded numbers of monocytes to lymphocytes stimulated with either tetanus toxoid or phytohemagglutinin. By nonparametric analysis, it was determined that a significantly greater number of monocytes was required for half-maximal responses of lymphocytes from subjects with PGL (for tetanus toxid but not phytohemagglutinin) and from those with AIDS, compared with healthy subjects. To address whether this observed difference was a result of a defect in accessory function of monocytes or a result of altered responsiveness of lymphocytes, a mixing experiment was performed between monocytes and lymphocytes obtained from a patient with PGL but without symptoms and an HLA-D-matched healthy sib. Dysfunction of both monocytes and lymphocytes was evident. Thus, this report provides data that monocytes in HIV infection are defective in accessory function for lymphocyte responses to soluble stimuli. We speculate that such dysfunction of monocytes may contribute to the progressive disturbance of the immune response that occurs during HIV infection.