Picotamide is an antiplatelet drug with a dual inhibitory action. Thus, picotamide inhibits both thromboxane A2 (TxA2) receptors and TxA2 synthase and, at variance with aspirin, does not interfere with endothelial prostacyclin (PGI2) production. Two large randomized trials have been performed to assess the clinical efficacy of picotamide in patients at risk of atherothrombosis. The ADEP study compared peripheral artery disease (PAD) patients randomized to picotamide or placebo. This study did not show a significant reduction of cardiovascular events by picotamide but a subgroup analysis showed its potential usefulness in patients with diabetes. To investigate this issue further, the DAVID study recently enrolled diabetic patients with PAD randomized to picotamide versus aspirin; the results showed a significant reduction of overall mortality in the picotamide group. Moreover long-term picotamide treatment in diabetes promotes the reduction of microalbuminuria and the inhibition of growth of carotid plaques. These data suggest that picotamide may represent an interesting drug to be further investigated in future trials in the atherothrombotic setting.