Tuberculous pleural effusions are characterized by lymphocytosis; the significance of mesothelial cells is uncertain, as are the cytologic features in concurrent human immunodeficiency virus (HIV) infection. This blinded study compared 38 culture-positive pleural fluids (6 HIV+) with 38 controls from benign exudative processes. Logistic regression analysis selected mature lymphocytes as most predictive of positive culture, and mesothelial cells and eosinophils as negative predictors. Mesothelial cells were scant (< 10% of nucleated cells) in 36/38 cases with mycobacteria (sensitivity 95%); if these cell were > 10%, tuberculosis was virtually ruled out in HIV- patients. Specificity was maximized (82%) when mesothelial cells < 10% were combined with lymphocytes > 50%; positive predictive value with this combination was 76%, but was raised to 96% if moderate/marked cellularity was also identified. Among tuberculosis cases, reactive mesothelial cells differentiated HIV+ from HIV- patients; there was no other significant difference.