The contribution of postimplant optimization of device settings to the beneficial effect of cardiac resynchronization therapy (CRT) in heart failure is uncertain. We performed a meta-analysis to investigate the impact of CRT optimization on the improvement of left ventricular function, exercise capacity, and quality of life. We undertook a systemic review of the evidence from a search of relevant controlled clinical studies in the MEDLINE and EMBASE databases. Changes in left ventricular ejection fraction (LVEF), 6-minute walk distance, and Minnesota Living with Heart Failure score at follow-up were assessed; the primary outcome was ejection fraction. A random-effects model was used to combine weighted mean difference (WMD) and 95% confidence intervals (CIs). A metaregression was undertaken to assess the impact of potential covariates. Data were collated from 13 studies enrolling 1,431 patients (919 optimized and 669 controls). Pooled analysis demonstrated that the optimization procedure resulted in a significant increase in LVEF (WMD 2.6%, 95% CI 0.8 to 4.4, p = 0.001) as compared with a nonoptimized CRT. No improvements with the optimization of CRT were seen in 6-minute walk distance and quality of life (WMD 12 m, 95% CI 23 to 48, p = 0.49, and 3.6, 95% CI 2.2 to 9.5, p = 0.22, respectively); however, this part of the analysis was performed using limited data. Thus, these collated data suggest that the optimization of CRT leads to a significant but small improvement in LVEF in patients with heart failure. Additional, adequately powered studies are needed to evaluate the effects of this procedure on exercise tolerance and quality of life.