Background: Microplegia delivers blood and additives for cardioplegia with minimal crystalloid. We retrospectively compared microplegia with standard 8:1 blood cardioplegia with a propensity-matched analysis in patients undergoing isolated coronary artery bypass graft (CABG) surgery. Methods: Prospectively collected data for 2,630 consecutive patients who underwent isolated CABG surgery (2004 to 2006) with the exclusive use of microplegia was compared with an equivalent 3-year cohort (1998 to 2000) of 5,058 consecutive isolated CABG patients with the exclusive use of 8:1 diluted blood cardioplegia. Propensity score matching identified 1,980 matched pairs (in each group) for analysis. Results: In the matched groups, the hospital mortality was identical (1.2%). The prevalence of low cardiac output syndrome was significantly (p< 0.001) lower in the later period when microplegia was employed (2.7%) compared with the standard cardioplegia group (5.0%). Although these results may also reflect improvements in care with time, a multivariable logistic regression analysis of the entire cohort (not matched) also demonstrated a twofold independent reduction in low cardiac output syndrome in microplegia patients (odds ratio, 1.9; 95% confidence interval 1.4 to 2.5). Conclusions: Compared with 8:1 blood cardioplegia, microplegia during isolated CABG surgery was associated with a lower incidence of postoperative low cardiac output syndrome. Microplegia may reduce postoperative cardiac edema, increase buffering, and permit more rapid recovery of ventricular function. Randomized trials are required to determine whether the relationship between microplegia and reduced low output syndrome is causal or is merely an association.