Maintenance therapy post-autologous hematopoietic cell transplantation (AHCT) with either lenalidomide or bortezomib for multiple myeloma (MM) have separately been shown to improve progression-free survival (PFS), but have never been directly compared. We performed a retrospective study to investigate progression-free and overall survival outcomes and toxicities of lenalidomide maintenance therapy compared with bortezomib maintenance in MM patients post-AHCT. This study included 156 patients who received post-AHCT lenalidomide or bortezomib maintenance therapy for MM. The primary outcome was PFS. Ninety-two patients received lenalidomide maintenance and 64 received bortezomib maintenance post-AHCT. By multivariable analysis, maintenance therapy choice and cytogenetics risk did not impact PFS or OS. Staging by International Staging System and pre-maintenance disease response were the greatest predictors for PFS. Treatment-related toxicities were as anticipated with 5.4% of patients receiving maintenance lenalidomide experiencing secondary primary malignancies (SPMs) compared with 3% for bortezomib. These findings suggest there were no differences in PFS or OS between lenalidomide and bortezomib maintenance therapy options for post-transplantation MM patients. These data should be validated in a larger, prospective cohort to determine if maintenance choice should be guided by side effect profile and patient anticipated tolerance rather than by disease biology alone.