Summary. Background: Poor response to both aspirin and clopidogrel (dual poor responsiveness [DPR]) is a major risk factor for recurrent ischemic events. Objectives: The aim of this study was to identify factors associated with DPR, defined with specific tests, and derive a predictive clinical score. Methods: We studied 771 consecutive stable cardiovascular patients treated with aspirin (n = 223), clopidogrel (n = 111), or both drugs (n = 437). Aspirin responsiveness was evaluated by serum thromboxane (Tx)B2 assay, and clopidogrel responsiveness by calculating the platelet reactivity index (PRI) on the basis of the phosphorylation status of the vasodilator phosphoprotein. The analysis was focused on patients treated with both drugs, and on independent predictors of DPR. Results: Among patients on dual therapy, there was no relevant correlation between TxB2 levels and PRI values (r = 0.11). Sixty-seven patients (15.4%) had DPR. Diabetes [odds ratio (OR) 1.89, 95% confidence interval (CI) 1.06–3.39], high body weight (> 86 kg vs. < 77 kg, OR 4.74, 95% CI 2.49–9.73), low aspirin dose (75–81 mg vs. ≥ 160 mg, OR 0.12, 95% CI 0.09–0.93) and high C-reactive protein (CRP) level (> 1.6 mg L−1 vs. < 0.6 mg L−1, OR 3.66, 95% CI 1.74–8.72) were independently associated with DPR, via increased TxB2 levels, increased PRI, or both. These associations with TxB2 and PRI were reproduced across the whole population. With use of a factor-weighed score (c-index = 0.74), the predicted prevalence of DPR was 57% in the highest strata of the score as compared with < 4% for the lowest strata. Conclusions: Diabetes, body weight, the aspirin dose and CRP levels are readily available independent predictors of DPR, and some are potential targets for reducing its prevalence.