Despite high response rates, anti-PD-1 therapy monotherapy eventually fails in most patients with relapsed or refractory Hodgkin Lymphoma (HL) and is generally ineffective in most other B-cell malignancies. The lymphocyte activation gene 3 (LAG-3) cell-surface receptor represents another immune checkpoint molecule that can be targeted to induce remissions in these diseases; dual inhibition of PD-1 and LAG-3 is approved for treating advanced melanoma. We performed a multicenter phase 1/2a open-label study of the anti-LAG-3 antibody relatlimab (RELATIVITY-022) administered as monotherapy or in combination with nivolumab in patients with relapsed or refractory B-cell malignancies. In total, 106 patients were treated and no dose limiting toxicities were observed during escalation. The recommended phase 2 dose was relatlimab 240 mg as monotherapy or nivolumab 240 mg plus relatlimab 160 mg, administered every 2 weeks. No unexpected safety signals were observed compared to single agent anti-PD-1 therapy. In the HL expansion cohorts, overall response rate (ORR) was 62% and complete response rate (CRR) was 19% in anti-PD-(L)1 naïve patients (n = 21), with a median PFS of 19 months; ORR was 15% and CRR 0%, median PFS 6 months in anti-PD-(L)1 progressed patients (n = 20). In the DLBCL cohort, ORR was 7% with no CRs (n = 15), and median PFS was 2 months. Nivolumab plus relatlimab appeared to be safe and tolerable. Efficacy in PD-1 naïve HL patients was encouraging, although the contribution of relatlimab to overall efficacy of the combination needs to be further evaluated. Clinicaltrials.gov; NCT02061761.