Background and Purpose — Guidelines for medical practice in stroke have been proposed in different countries, but their impact on stroke outcome has not been verified to date. The aim of this study was to evaluate the impact of the American Heart Association guidelines for acute stroke and for transient ischemic attack on first-ever stroke patients. Methods — Three hundred eighty-six first-ever ischemic stroke patients were admitted to the study. Those observed within 6 hours from stroke onset were eligible for the acute clinical phase of the study, while all were admitted to the early clinical phase. The follow-up lasted 6 months. Primary end points were survival and the effectiveness of treatment on disability, measured as the proportion of potential improvement in the Barthel Index score achieved during treatment. A rating of noncompliance with the guideline recommendations was calculated for each patient, and its association with the end points was investigated. The Kaplan-Meier method and log-rank test were used to estimate and compare survival curves between groups; Cox proportional hazards model and logistic regression were used to identify risk factors for mortality; and correlation tests and regression analysis were used to evaluate the influence of guideline compliance on disability. Both univariate and multivariate statistical analyses were performed. Results — Survival and treatment effectiveness were directly correlated with guideline compliance. The relative risk of death for patients with a noncompliance rating ≥5 was 2.26 with respect to patients with a noncompliance rating <5 (95% CI, 1.51 to 4.67; P <0.0007). In this latter group, at 6 months we detected a 15% decrease in mortality (95% CI, 9.1% to 17.5%). Treatment effectiveness showed a Spearman’s rank correlation with the noncompliance rating of −0.3 ( P <0.001). At discharge we observed a 13% increase in treatment effectiveness, while no significant differences were detectable at 3 and 6 months. These associations were confirmed by the multivariate analysis, in which we included, together with the noncompliance rating, all the variables previously identified as independent predictors of mortality and disability. Conclusions — This study demonstrates an association between adherence to guidelines and stroke outcome, and it can be viewed as a study that prepares the way for a randomized controlled trial in this area. It also emphasizes the need to develop personnel and structures devoted to stroke care because an evidence-based clinical approach could significantly reduce the risk of death.