BACKGROUND. High-dose interferon (INF)-α-2b is the only Food and Drug Administration-approved adjuvant treatment for patients with melanoma who are at high risk of recurrence. Although circumstantial evidence points to a potentially harmful effect of INF-α-2b on platelet function, to the authors' knowledge this has never been studied in humans. METHODS. The study group was comprised of patients who had undergone surgery for melanoma and were free of disease but at a high risk of recurrence. All patients were candidates for adjuvant INF treatment (high-dose) and were undergoing routine evaluation to which platelet aggregation was added. Aggregation was triggered in standard fashion with adenosine diphosphate, epinephrine, collagen, thrombin, arachidonic acid, and ristocetin. Blood samples were drawn immediately before treatment, during the intravenous loading phase, during the subcutaneous maintenance phase, and 3-6 weeks after cessation of treatment. Patients receiving low-dose, long-standing INF-α-2b treatment also were tested. All results at each phase were compared with those of normal controls. RESULTS. In those patients receiving high-dose INF-α-2b, ristocetin- induced aggregation did not appear to be affected. However, the response to ≥ of the other agonists was impaired in 5 of 6 samples during loading, 14 of 15 samples during the maintenance phase, and 8 of 13 samples after treatment, compared with only 1 of 8 samples before treatment (P = 0.025, P = 0.002, and P = 0.067, respectively). During treatment with low-dose INF, platelet function was affected to a lesser extent. CONCLUSIONS. INF treatment in melanoma patients appears to be associated with severe impairment of platelet aggregation, which appears to be dose-dependent and cumulative- dose -dependent. This is not detectable by the standard coagulation profile. This effect has significant implications in the event of accidental injury or elective surgery. The antiaggregation activity may be the mechanism by which INF delays, reduces, or prevents the formation of melanoma metastases.