Inotuzumab ozogamicin (CMC‐544), a humanized anti‐CD22 antibody conjugated to the potent cytotoxic antibiotic calicheamicin, targets the CD22 antigen expressed on the majority of B‐cell non‐Hodgkin lymphomas. This phase I study assessed the tolerability, safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin administered intravenously in combination with rituximab in Japanese patients with relapsed or refractory B‐cell non‐Hodgkin lymphoma. Ten patients were administered rituximab 375 mg/m² followed by inotuzumab ozogamicin at the maximum tolerated dose (1.8 mg/m²). Treatment was repeated every 28 days up to eight cycles, or until occurrence of disease progression or intolerable toxicity. The safety profile was similar to that of inotuzumab ozogamicin monotherapy, with hematologic adverse events occurring most frequently. The most common grade three or higher adverse events were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). The overall response rate was 80% (8/10; 95% CI, 44–98%). Drug exposure increased with successive doses, similar to the pharmacokinetic profiles observed in previous phase I monotherapy studies. Efficacy results suggested promising antitumor activity, and the overall findings support the continued clinical development of this therapeutic regimen in patients with relapsed or refractory B‐cell non‐Hodgkin lymphoma. This trial was registered at www.ClinicalTrials.gov as NCT00724971. (Cancer Sci 2012; 103: 933–938)