Background We performed a pilot study of daratumumab (monoclonal antibody directed against CD38) in muscle invasive bladder cancer (MIBC) and treatment refractory metastatic renal cell carcinoma (mRCC). Methods Patients with MIBC underwent baseline TURBT followed by 4 weekly doses of daratumumab prior to cystectomy. Patients with mRCC underwent a baseline and a sequential biopsy after 8 weekly doses. The primary endpoint was safety. The secondary endpoints: MIBC pathologic complete response rate (pCR), mRCC: objective response rate (ORR) and progression free survival (PFS). Exploratory analyses included immune monitoring. A Bayesian sequencing monitoring design for toxicity was used for excessive toxicity (TOX). Results: In both the MIBC (n=8) and mRCC (n= 8), no TOX events were encountered. In the MIBC cohort, 1 patient experienced pCR. In mRCC, no objective responses and the median PFS was 1.5 months (95%CI: 1.1, 1.8 months). Immune monitoring found significant reductions in NK cells in circulation in both cohorts' post treatment. In the tissue analysis, IHC found evidence of diminished CD38 presence in mRCC with treatment, while baseline levels in MIBC were low. Conclusions Treatment with daratumumab was safe. No signal of efficacy was detected in mRCC and conclusions on activity in MIBC were limited. Evidence of daratumumab targeting CD38 was detected in circulating immune cells and within the tumor microenvironment of mRCC and MIBC.