The objective of this study was to test a low dose of (25 mg weekly) of the mammalian target of rapamycin kinase inhibitor temsirolimus for patients with relapsed mantle cell lymphoma (MCL). Patients with relapsed or refractory MCL were eligible to receive temsirolimus 25 mg intravenously every week as a single agent. Patients who had a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission and then were observed without maintenance. Of 29 enrolled patients, 28 were evaluable for toxicity, and 27 were evaluable for efficacy. The median age was 69 years (range, 51-85 years), 86% of patients had stage IV disease, and 71% had > or = 2 extranodal sites. Patients had received a median of 4 prior therapies (range, 1-9 prior therapies), and 50% were refractory to the last treatment. The overall confirmed response rate was 41% (11 of 27 patients; 90% confidence interval CI, 22%-61%) with 1 complete response (3.7%) and 10 partial responses (37%). The median time to progression in all eligible patients was 6 months (95% CI, 3-11 months), and the median duration of response for the 11 responders was 6 months (range, 1-26 months). Hematologic toxicities were the most common, with 50% (14 of 28 patients) grade 3 and 4% (1 of 28 patients) grade 4 toxicities observed. Thrombocytopenia was the most frequent cause of dose reduction. Single-agent temsirolimus at a dose of 25 mg weekly is an effective new agent for the treatment of MCL. The 25-mg dose level retained the antitumor activity of the 250-mg dose with less myelosuppression. Further studies of temsirolimus in combination with other active drugs for MCL and other lymphoid malignancies are warranted.