CD47 overexpression has been associated with tumor cell survival. We present the safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of evorpacept, a novel fusion protein comprising a high-affinity CD47-SIRPα immune checkpoint inhibitor to promote tumor cell phagocytosis and inactive Fc domain to spare healthy cells, plus rituximab in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) from the phase I ASPEN-01 study. Thirty-three patients received intravenous evorpacept (10 mg/kg [N=22] or 15 mg/kg [N=11] once weekly) until disease progression, in combination with fixed-duration intravenous rituximab (375 mg/m2 once weekly for 4 weeks, then every 4 weeks for 8 months). Evorpacept plus rituximab was well tolerated, with no dose-limiting toxicities; no maximum tolerated dose was identified. The most common treatment-related adverse events (TRAE) were rash (24.2%) and fatigue (15.2%); most TRAE (70.0%) were mild-to-moderate in severity. Four (12.1%) patients reported grade 3 TRAE: anemia, neutropenia, decreased neutrophil count, increased alanine aminotransferase, decreased lymphocyte count, and decreased platelet count (1 of each). Two (6.1%) patients experienced grade 4 TRAE (neutropenia, decreased neutrophil count). Six (18.2%) patients experienced serious AE (not treatment-related): asthma, dyspnea, respiratory failure, gastrointestinal infection, pneumonia, cardiac failure, and disease progression (1 of each). Two (6.1%) deaths occurred (not treatment-related). Pharmacokinetics/ pharmacodynamics were consistent with previous studies, with complete CD47 target occupancy (≥85%) achieved at both doses. In response-evaluable patients (N=32), objective response rate was 50.0% (95% confidence interval: 33.1-69.8%). The safety, tolerability, and promising anti-tumor activity of evorpacept plus rituximab support continued evaluation of this combination in NHL (clinicaltrials gov. Identifier: NCT03013218).