Recent clinical evidence has indicated that the severity of atherosclerosis is correlated with the level of soluble ICAM-1 (sICAM-1). Nitric oxide (NO) donors are used to treat patients with stable angina pectoris, and the aim of this study was to investigate the short- and long-term effect of molsidomine on the level of this circulating biochemical marker of endothelial function. We included 172 patients and examined the effect of the NO donor treatment on angina related parameters and on sICAM-1 levels after a 4-week- and a 1-year treatment period. After 4 weeks, angina attacks and sublingual (s.l.) isosorbide dinitrate tablet (ISDN) consumption frequency was significantly ( p < 0.0001) reduced without altering sICAM-1 levels when compared to the baseline values. The anti-anginal effect of molsidomine 16 mg once a day (o.a.d.) was sustained (s.l. ISDN consumption) or improved (angina attacks frequency; p < 0.002) during the following year and a significant decrease in sICAM-1 levels ( p < 0.0001) was observed. When the sICAM-1 changes during the 1-year treatment period were distributed in four categories (quartiles of the distribution), it was demonstrated that the decrease in s.l. ISDN consumption between the start and the end, was most pronounced in the group with the largest sICAM-1 decrease (fourth quartile of distribution; p = 0.038). In conclusion, the reduction in the pro-inflammatory marker sICAM-1 after 1-year daily treatment with molsidomine may indicate that this NO donor besides its anti-anginal function, promotes a less activated state of the endothelium in patients with stable angina.