While guidelines for preventing chemotherapy-induced nausea and vomiting (CINV) are widely available, clinical uptake of guidelines remains low. Our objective was to evaluate the effect of guideline-consistent CINV prophylaxis (GCCP) on patient outcomes. This prospective, observational multicenter study enrolled chemotherapy-naive adults initiating single-day highly or moderately emetogenic chemotherapy (HEC or MEC) for cancer. Patients completed 6-day daily diaries beginning with cycle 1 for up to three chemotherapy cycles. The primary study end point, complete response (no emesis and no use of rescue therapy) during 120 h after cycle 1 chemotherapy, was compared between GCCP and guideline-inconsistent CINV prophylaxis (GICP) cohorts using multivariate logistic regression, adjusting for potential confounding factors. In cycle 1 (N=991), use of GCCP was 55% and 46% during acute and delayed phases, respectively, and 29 % for the overall study period (acute plus delayed phases). Complete response was recorded by 172/287 (59.9%) and 357/704 (50.7%) patients in GCCP and GICP cohorts, respectively (P=0.008). The adjusted odds ratio for complete response was 1.43 (95% confidence interval 1.04-1.97; P=0.027) for patients receiving GCCP versus GICP. GCCP reduces the incidence of CINV after single-day HEC and MEC.