Prostate cancer and chronic lymphocytic leukemia (CLL) are relatively common malignancies associated with advanced age. Although immunotherapy-based strategies are used to treat both, currently, there is no overlap in specific therapies. Sipuleucel-T is an active cellular immunotherapy that improves overall survival for patients with metastatic castration resistant prostate cancer (mCRPC) but is not typically associated with a decline in prostate-specific antigen (PSA) following administration. We report the case of a 78-year-old man with mCRPC and Rai stage 0 CLL who sustained a 12-month decline in both PSA and white blood cell (WBC) count following treatment with APC8015-2 (an investigational form of sipuleucel-T), as part of the phase II ProACT clinical trial. Two years later, the patient received commercial sipuleucel-T and again was noted to have a decline in PSA. Exploratory analysis did not clearly identify any peripheral immune markers associated with response. This case report suggests that treatment with sipuleucel-T can rarely lead to PSA decline, may have dual activity against both prostate cancer and CLL, and that these findings warrant further investigation.