BACKGROUND Mantle cell lymphoma (MCL) is aggressive, and relapsed/refractory disease has poor outcomes. PATIENTS AND METHODS Thirty-nine patients (men = 34, women = 5) at 64 (41-82) years of age with relapsed/refractory MCL, ineligible for high-dose chemotherapy and had received 2 (1-5) prior regimens, were treated with a continuous oral regimen, comprising oral arsenic trioxide (oral-As2O3), chlorambucil and ascorbic acid. RESULTS Overall response rate was 49% (complete response, CR = 28%; partial response, PR = 21%). Only grade 1/2 toxicities were observed (hematologic: 56%, hepatic: 8%). Response was maintained in 11 patients (CR = 8; PR = 3), after a median of 24 (2-108) months. Independent prognostic factors for response were increased lactate dehydrogenase (P = 0.04) and unfavorable MCL international prognostic index (P = 0.04). At a median follow-up of 21 (1-118) months, the median progression-free survival (PFS) was 16 months, and overall survival (OS) 38 months. Independent prognostic factors for PFS were female gender (P = 0.002), and Eastern Cooperative Oncology Group (ECOG) performance score of 2 (P = 0.009). Independent prognostic factors for OS were female gender (P < 0.001), ECOG performance score of 2 (P = 0.03), non-response (P < 0.001), and disease progression after initial response (P = 0.05). CONCLUSION An oral regimen of oral-As2O3, chlorambucil and ascorbic acid was active with minimal toxicity in relapsed/refractory MCL, achieving durable responses in ∼30% of cases.