This study's objective was to determine the efficacy and safety of gemcitabine in patients with relapsed or chemotherapy-refractory Hodgkin's lymphoma (HL). Twenty-nine patients were enrolled. Eight of the first 10 patients received intravenous gemcitabine (1250 mg/m2) days 1, 8, and 15 every 4 weeks. Two patients withdrew consent before treatment. Because of toxicity, the remaining 19 patients received 1000 mg/m2 on days 1 and 8 every 3 weeks. Of the 29 treated patients, 16 (55.2%) were male, the median age was 43 years (range, 20.9-77.3), and 89.7% of them were white. Twelve patients (41.4%) had an Eastern Cooperative Oncology Group performance status (PS) of 0, 14 (48.3%) had a PS of 1, and 3 (10.3%) had a PS of 2. All patients had >/= 2 prior chemotherapy regimens. Eighteen patients (62%) had a relapse following bone marrow transplantation. Of 27 evaluable patients, 6 (22%) had partial response, 14 (52%) had stable disease, and 7 (26%) had progressive disease. The median time to progression for all patients was 6.4 months (range, 1.1-21.9). The median survival for all patients was 26.9 months (range, < 1-28.4). All patients have discontinued treatment because of disease progression or relapse. Grade >/= 3 toxicity occurred in 14 patients (48.3%): thrombocytopenia (33.3%), neutropenia (29.6%), anemia (7.4%), increased alanine aminotransferase, reduced cardiac function, and fever (3.7% for each event). This study confirms the activity of gemcitabine in relapsed and highly refractory HL. Dose and schedule may be modified in the future to optimize responses. As gemcitabine is active in highly refractory/relapsed HL, future studies should consider incorporating gemcitabine in combination regimens as first-line therapy for patients with high-risk HL.