This open-label phase III trial, a companion to an earlier placebo-controlled trial, evaluated safety and efficacy of denileukin diftitox (DD) in patients with cutaneous T-cell lymphoma (CTCL) who relapsed after responding to DD primary treatment in the earlier trial. Twenty relapsed patients (stages IA-III) received DD 18 μg/kg/day intravenously on days 1-5 of a 21-day cycle, for ≤ 8 cycles. Efficacy was assessed monthly during the first year then every 3 months. The overall response rate was 40%, mostly partial responses. Nine patients (all baseline stages ≤ IIA) experienced progression. Intent-to-treat median progression-free survival was 205 days, and median duration of response was 274 days. The most common adverse events were nausea, upper respiratory tract infections, fatigue and rigors. Three patients withdrew because of toxicity. This study showed that DD may provide clinically meaningful benefit in patients with CTCL who relapsed after initial response to DD.