We evaluated long-term outcomes of 60 patients with chronic lymphocytic leukemia treated with an initial therapy of lenalidomide. At a median follow-up of 4 years, time-to-treatment failure has not been reached and overall survival is 82%. Thirty-five (58%) patients had a response lasting >36 months (long-term responders [LTRs]). Best LTR responses consisted of 25 (71%) complete remissions and 10 (29%) partial remissions. In addition to clinical responses, an increase in IgA, IgG, and IgM levels of >50% from baseline was reported in 61%, 45%, and 42% of LTRs. Normalization in the percentage of CD4+ and CD8+ cells and T-cell numbers was observed in 48%, 71% and 99% of LTRs. Compared with other patients in the study, LTRs had lower baseline plasma levels of β-2-microglobulin, were more likely to have trisomy 12, and less likely to have deletion 17p. This trial was registered at http://clinicaltrials.gov as # NCT00535873.