Objective Custodiol® and St. Thomas cardioplegia are widely employed in mini-thoracotomy mitral valve (MV) operations. One-dose of the former provides 3 h of myocardial protection. Conversely, St. Thomas solution is usually reinfused every 30 min and safety of single delivery is unknown. We aimed to compare single-shot St. Thomas versus Custodiol® cardioplegia. Methods Primary endpoint of the prospective observational study was cardiac troponin T level at different post-operative time-points. Propensity-weighted treatment served to adjust for confounding factors. Results Thirty-nine patients receiving St. Thomas were compared with 25 patients receiving Custodiol® cardioplegia; cross-clamping always exceeded 45 min. No differences were found in postoperative markers of myocardial injury. Ventricular fibrillation at the resumption of electric activity was more frequent following Custodiol® cardioplegia ( P  = .01). Conclusion Effective myocardial protection exceeding 1 h of ischemic arrest can be achieved with a single-dose St. Thomas cardioplegia in selected patients undergoing right mini-thoracotomy MV surgery.