Hemorrhagic cystitis (HC) is an important complication after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide (PT-CY). Sodium 2-mercaptoethanesulfonate (MESNA) can prevent bladder injury when given with PT-CY. However, the best way to deliver MESNA is not known. This study assessed the incidence of HC after haplo-HSCT with PT-CY with 2 different methods of MESNA administration. The cumulative incidence of HC was lower in patients who received MESNA as a continuous infusion compared with those who received it as an intermittent bolus (5.6% versus 27.8%; P = .01). MESNA administration as an infusion was associated with a lower risk of developing HC (hazard ratio [HR], .19; 95% confidence interval [CI], .04 to .86; P = .02) on univariate analysis. This effect remained significant after adjustment in multivariate analysis (HR, .21; 95% CI, .04 to .88; P = .03). MESNA delivered as a continuous infusion is a simple and potentially useful way to prevent HC after PT-CY.