Recently, lenalidomide and low dose dexamethasone were found to result in superior overall survival compared to lenalidomide and high dose dexamethasone. The immune suppressive effects of dexamethasone can antagonize lenalidomide immunomodulatory activity and may explain this observation. We conducted a retrospective analysis to evaluate the single agent activity of lenalidomide in newly diagnosed myeloma. Records of patients with newly diagnosed symptomatic multiple myeloma treated with single agent lenalidomide at H. Lee Moffitt Cancer Center and Roswell Park Cancer Institute were reviewed. Data were collected on disease characteristics, demographics, and treatment outcomes. Responses were assessed as per the International Myeloma Working Group criteria. From March 2007 to July 2009, 17 patients with newly diagnosed multiple myeloma were treated with single agent lenalidomide at both institutions. The median age was 70 years (range 46–84 years). Lenalidomide was generally well tolerated and no grade 4 hematologic toxicities were noted. The overall response rate (≥partial remission) to lenalidomide alone was 47% at a median follow-up of 7 months (range 1–26). This experience suggests that lenalidomide alone can induce an anti-myeloma effect in previously untreated patients who are considered poor candidates for concurrent dexamethasone.