A high clot burden score (CBS) is associated with favorable outcome after intravenous treatment for acute ischemic stroke. The added benefit of intra-arterial treatment might be less in these patients. The aim of this exploratory post hoc analysis was to assess the relation of CBS with neurological improvement and endovascular treatment effect. For 499 of 500 patients in the MR CLEAN study (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), the CBS was determined. Ordinal logistic regression models with and without main baseline prognostic variables were used to assess the association between CBS (continuous or dichotomized at CBS of 6) and a shift toward better outcome on the modified Rankin Scale. The model without main baseline prognostic variables only included treatment allocation and CBS. Models with and without a multiplicative interaction term of CBS and treatment were compared using the χ2 test to assess treatment effect modification by CBS. Higher CBS was associated with a shift toward better outcome on the modified Rankin Scale; adjusted common odds ratio per point CBS was 1.12 (95% confidence interval, 1.04-1.20]. Dichotomized CBS had an adjusted common odds ratio of 1.67 (95% confidence interval, 1.12-2.51). Both effect estimates were slightly attenuated by adding baseline prognostic variables. The addition of the interaction terms did not significantly improve the fit of the models. There was a small and insignificant increase of intra-arterial treatment efficacy in the high CBS group. A higher CBS is associated with improved outcome and may be used as a prognostic marker. We found no evidence that CBS modifies the effect of intra-arterial treatment. URL: http://www.trialregister.nl. Unique identifier: NTR1804. URL: http://www.controlled-trials.com. Unique identifier: ISRCTN10888758.