Purpose <p>Postoperative pulmonary complications are common and associated with worse long-term outcomes. In our previous trial, prophylactic penehyclidine inhalation reduced pulmonary complications in high-risk patients. Herein, we tested the hypothesis that penehyclidine inhalation might also improve long-term survival after surgery.</p> Methods <p>This was a long-term follow-up of a randomized trial. We enrolled 864 patients aged more than 50&#xa0;years who were scheduled for major upper-abdominal or non-cardiac thoracic surgery and judged to be at high risk of pulmonary complications. Participants were randomized to receive either penehyclidine or placebo inhalation during the perioperative period. The primary endpoint was overall survival after surgery. Secondary endpoints included recurrence-free and event-free survivals. </p> Results <p>Among patients included in the underlying trial, 826 (mean age 64&#xa0;years, 63.0% male, and 87.2% had cancer surgery) completed long-term follow-up (median 56&#xa0;months). At the end of the follow-up period, there were 132 deaths among 417 patients (31.7%) given penehyclidine compared with 127 deaths among 409 patients (31.1%) given placebo (hazard ratio 1.01; 95% CI 0.79–1.28;&#xa0;<i>P</i> = 0.958). Recurrence-free survival was 153/417 (36.7%) with penehyclidine versus 147/409 (35.9%) with placebo (hazard ratio 1.01; 95% CI 0.81–1.27;<i> P</i> = 0.934). Event-free survival was 187/417 (44.8%) with penehyclidine versus 174/409 (42.5%) with placebo (hazard ratio 1.04; 95% CI 0.85–1.28; <i>P</i> = 0.689).</p> Conclusions <p>In high-risk patients undergoing major upper-abdominal or non-cardiac thoracic surgery mainly for cancer, prophylactic penehyclidine inhalation did not improve long-term survival. Current evidence does not support its routine perioperative use to enhance long-term outcomes in this population.</p> Trial registration <p>ClinicalTrial.gov Identifier: NCT03868709; March 3, 2019.</p>