Hypotension occurs during cardiopulmonary bypass (CPB), in part because of induction of the inflammatory response, for which nitric oxide and guanylate cyclase play a central role. In this study we examined the hemodynamic effects of methylene blue (MB), an inhibitor of guanylate cyclase, administered during cardiopulmonary bypass (CPB) to patients taking angiotensin-converting enzyme inhibitors. Thirty patients undergoing cardiac surgery were randomized to receive either MB (3 mg/kg) or saline (S) after institution of CPB and cardioplegic arrest. CPB was managed similarly for all study patients. Hemodynamic data were assessed before, during, and after CPB. The use of vasopressors was recorded. All study patients experienced a similar reduction in mean arterial blood pressure (MAP) and systemic vascular resistance (SVR) with the onset of CPB and cardioplegic arrest. MB increased MAP and SVR and this effect lasted for 40 minutes. The saline group demonstrated a persistently reduced MAP and SVR throughout CPB. The saline group received phenylephrine more frequently during CPB, and more norepinephrine after CPB to maintain a desirable MAP. The MB group recorded significantly lower serum lactate levels despite equal or greater MAP and SVR. In conclusion, administration of MB after institution of CPB for patients taking angiotensin-converting enzyme inhibitors increased MAP and SVR and reduced the need for vasopressors. Furthermore, serum lactate levels were lower in MB patients, suggesting more favorable tissue perfusion.