The effect of methylprednisolone on fresh cells from patients with chronic lymphocytic leukaemia (CLL) has been studied using the differential staining cytotoxicity (DiSC) assay resulting in LC90S of < 0.2 to 2,000 µg/ml. Cells from previously treated patients were, on average, significantly more sensitive to methylprednisolone than those from untreated patients (mean LC90 = 5.7 µg/ ml, n = 61 vs 31.0 µg/ml, n = 17, respectively; p < 0.05). Twelve patients with advanced disease were given high-dose methylprednisolone (1 g/m2/day i.v. × 5 days). In 7 cases, > 3 courses were given; 3 patients did not respond (2 achieved palliation) and 4 (57%) achieved a good partial response. These latter 4 patients were all clinically resistant to chlorambucil and anthracyclines and 2 were resistant to fludarabine. In 5 cases, 1 or 2 courses were given but no patients responded. The 8 nonresponders survived a median of 3.5 months whilst the responders have survived a median of 28.5+ months (3 of 4 still alive). This work suggests a rationale for why CLL patients resistant to standard chemotherapy may benefit from high-dose methylprednisolone therapy. Due to cost and toxicity associated with therapy, the decision to treat would be best made on the basis of a DiSC assay result. This pilot study requires confirmation with a well-designed controlled clinical trial.