BACKGROUND: Controversy surrounds the optimal platelet aggregation measurement to assess clopidogrel non-responsiveness. The P2Y12 reactivity ratio (PRR) determined by vasodilator-stimulated phosphoprotein phosphorylation levels has been used to indicate the extent of P2Y(12) blockade. OBJECTIVES: We sought to compare the prevalence of non-responsiveness measured by maximum (MA) and 6 min aggregation (FA) and correlate these measurements with PRR in patients with non-responsiveness. METHODS: MA and FA were measured in stented patients (n=100) before and after clopidogrel treatment. The PRR was determined in 22 non-responsive patients. Responsiveness was defined as pre-treatment minus post-treatment aggregation; and non-responsiveness was defined as <10% change in platelet aggregation. RESULTS: Responsiveness was greater as determined by FA, p=0.006 (5 microM ADP) and p=0.003 (20 microM ADP)). There was a strong correlation between MA and FA stimulated by 5 microM (r=0.84, p<0.0001) and 20 microM ADP (r=0.90, p<0.001). The prevalence of non-responsiveness rose with agonist concentration but did not differ significantly between methods: 5 microM ADP [22% (MA) vs. 17% (FA), p=0.186] and 20 microM ADP [33% (MA) vs. 29% (FA), p=0.270]. PRR correlated with both MA (r=0.66, p<0.001) and FA (r=0.74, p<0.001) in non-responsive patients indicating incomplete receptor blockade. CONCLUSION: Clopidogrel responsiveness is higher when measured by FA as compared to MA. However, these measurements are equivalent in determining the prevalence of non-responsiveness: FA and MA are affected to the same degree in patients with non-responsiveness. These findings are relevant to ongoing studies assessing platelet inhibition by P2Y(12) inhibitors and support previous studies that employed MA to assess non-responsiveness.