We tested the ability of the differential staining cytotoxicity (DiSC) assay to discriminate between sensitive and resistant cell populations in human lymphatic neoplasms. First, the in vitro activity spectra of the most important drugs paralleled the known clinical activity spectra of the same agents. Second, there were highly significant correlations between in vitro chemosensitivity and the results of clinical chemotherapy. Third, specimens from previously untreated patients were significantly more sensitive to the most important drugs than were specimens from patients who had previously received chemotherapy. Finally, metachronous assays performed on specimens from the same patients showed little change in chemosensitivity if there had been no intervening chemotherapy between the times that the first and second assays were performed. However, if the patients had received intervening chemotherapy between the times of the first and second assays, the specimens in the second assays tended to be significantly more resistant than were the specimens in the first assays. These data indicate that the DiSC assay may be of value in the design of strategies to circumvent drug resistance in human lymphatic neoplasms.