This study compared iloprost and nifedipine to ascertain whether they could improve parameters of endothelial and platelet functions in the treatment of Raynaud's phenomenon secondary to systemic sclerosis. Thirteen patients affected by systemic sclerosis were treated with intravenous infusion of iloprost, and 7 patients were treated with oral nifedipine. Blood samples were taken at baseline and after 6 and 12 months of therapy to assess main serological indexes of endothelial damage, thrombin activation, fibrinolysis, as well as natural inhibitors of coagulation. After 12 months of therapy, the patients treated with iloprost had a significant decrease in thrombomodulin levels (p = 0.02) and a significant increase in tissue-plasminogen activator levels (p = 0.007), in comparison with the patients taking nifedipine (p = 0.007). Moreover, patients treated with nifedipine showed increased levels of thrombin-antithrombin complex after 12 months of therapy in comparison with baseline values (p = 0.03) and in comparison with the values of the patients treated with iloprost over the same period (p = 0.05). These preliminary results thus seem to indicate that iloprost plays an important, if at least partial, role in the protection and restoration of endothelial integrity in patients with systemic sclerosis.