© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Postoperative pain after cardiac surgery, exacerbated by cough and sternal mobilization, limits clearance of bronchopulmonary secretions and may predispose to postoperative pneumonia. In this study, we tested the ability of local anesthetic continuous wound infusion to prevent pneumonia after cardiac surgery with sternotomy and cardiopulmonary bypass (CPB) owing to better analgesia and bronchopulmonary drainage. Methods: In this randomized, double-blind, placebo-controlled trial conducted in five academic centers, patients undergoing cardiac surgery with sternotomy and CPB were enrolled from February 2012 until November 2014, and were followed over 30 days. Patients were assigned to a 48-h infusion (10 ml h −1 ) of l-bupivacaine (12.5 mg h −1 ) or placebo (saline) via a pre-sternal multiperforated catheter. Anesthesia and analgesia protocols were standardized. The primary end point was the incidence of pneumonia during the study period, i.e., until hospital discharge or 30 days. We hypothesized a 30% reduction in the incidence of pneumonia. Results: Among 1493 randomized patients, 1439 completed the trial. Pneumonia occurred in 36/746 patients (4.9%) in the l-bupivacaine group and in 42/739 patients (5.7%) in the placebo group (absolute risk difference taking into account center and baseline risk of postoperative pneumonia, − 1.3% [95% CI − 3.4; 0.8] P = 0.22). In the predefined subgroup of patients at high risk, l-bupivacaine decreased the incidence of pneumonia (absolute risk difference, − 5.6% [95% CI − 10.0; − 1.1], P = 0.01). Conclusions: After cardiac surgery with sternotomy, continuous wound infusion of l-bupivacaine failed to decrease the incidence of pneumonia. These findings do not support the use of local anesthetic continuous wound infusion in this indication. Further study should investigate its effect in high-risk patients. Trial registration: EudraCT Number: 2011-003292-10; Clinicaltrials.gov Identifier: NCT01648777.