Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in CAD patients without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n=22) or placebo (n=20) on Days 0 and 7, then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of Weeks 23, 25, 26], avoidance of transfusion and study-prohibited CAD therapy [Weeks 5-26]) were met by 16 patients (73%) on sutimlimab and three patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval 2.9, 88.0; P<0.001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by Week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at Week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment emergent adverse event. Headache, hypertension, rhinitis, Raynaud's phenomenon, and acrocyanosis were more frequent with sutimlimab versus placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued due to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. (ClinicalTrials.gov: NCT03347422).