Antiplatelet therapy is considered as a standard procedure against atherosclerotic cardiovscular disease but this therapy has limited effect if resistance to acetylsalicylic acid or clopidogrel is present. Important factors associated with resistance are gender; or inflammation possibly associated with membrane microparticles (MP). It was decided to challenge the hypothesis that differential responses to dual antiplatelet therapy are conditioned by gender and/or proinflammatory status. The study involved 160 patients with stable coronary heart disease (118 men, 42 women) aged 65.2 ± 7.8 years. Patients were treated long-term with acetylsalicylic acid (ASA); plus clopidogrel starting 6 days before percutaneous coronary intervention (both 75 mg/day). Response was evaluated using platelet aggregation with either arachidonic acid (the ASPI test; predominantly for ASA response) or adenosine diphosphate (the ADP test; predominantly for clopidogrel response). MP levels were measured as follows: total (MP-total); with TF expression (MP-TF); or platelet-derived microparticles (PDMP), as well as proinflammatory parameters: C-reactive protein (CRP), leukocytes (WBC) and platelet numbers (PLT). Analysis of platelet-aggregation levels with regard to gender revealed higher aggregation in women: with resistance to ASA (ASPI test: P = 0.0383, ADP test: P = 0.0027); resistance to clopidogrel (ASPI test: P = 0.0003; ADP test: P = 0.0566) and with sensitivity to both drugs with the ADP test (P = 0.0190). In women relative to men, regardless of response, significantly higher CRP (P = 0.0012), WBC (P = 0.0244) and PLT numbers (P = 0.0001) were found. In contrast, in men significantly higher concentrations of MP-TF (P = 0.0286) and triglycerides (P = 0.0296) were found in the clopidogrel-resistant group. We conclude that women have an inferior response to dual antiplatelet therapy relative to men, possibly associated with higher platelet reactivity (especially when measured with the ADP test), with a more accentuated proinflammatory status. In contrast, among the factors supporting the resistance in men can be an elevated concentration of MP-TF which, together with the coexistence of hypertriglyceridemia, may constitute an important mechanism of resistance to clopidogrel.