Objective: This study investigated the feasibility, timing and indications for closure of large muscular ventricular septal defects (VSDs) in infants without use of a cardiopulmonary bypass. Methods: A total of 9 infants with large muscular VSDs ranging in size from 7 to 15 mm were treated by minimally invasive closure without cardiopulmonary bypass between April 2010 and February 2013. Results: All surgeries were successful without resulting in uncontrolled systemic infection, a pulmonary hypertensive crisis or a severely low cardiac output, and with an apparently shorter operation time and postoperative tracheal cannula. Conclusions: VSD closure without cardiopulmonary bypass can improve the efficacy and prognosis of infants with large muscular VSDs and concurrent pulmonary infections or respiratory failure.