Asymmetric dimethylarginine (ADMA), myeloperoxidase (MPO) and paraoxonase 1 (PON1) are directly involved in the pathogenesis of atherosclerosis by modulation of oxidative stress and/or NO bioavailability. We aimed to assess whether endurance exercise which is known to be cardioprotective could beneficially affect these novel risk markers. Thirty-two subjects (31-68 yrs, 56% males) with elevated cardiovascular risk including ten patients with coronary artery disease volunteered for a supervised 12-week endurance training (196 +/- 15 min/week). Their fitness evaluated by 2 km test runs improved significantly after training (pre: 17.3 +/- 0.8 vs. post: 15.7 +/- 0.9 min, p < 0.001). ADMA (pre: 0.94 +/- 0.03 vs. post: 0.75 +/- 0.04 micromol l(-1)) and MPO (pre: 296.8 +/- 22.2 vs.post: 185.7 +/- 19.5 ng ml(-1)) serum levels decreased significantly by 17.6 +/- 4.6% and 28.5 +/- 7.5%, respectively, after training (both p < 0.001). Their down-regulation was inversely correlated (ADMA: r = -0.609, p < 0.001, MPO: r = -0.437, p = 0.014) with the up-regulation of plasma cGMP levels (Cyclic-guanosine 3',5'-monophosphate; pre: 1.6 +/- 0.12 vs. post: 2.21 +/- 0.2 micromol ml(-1), p = 0.001) reflecting NO production. PON1 activity towards phenylacetate was not significantly influenced by training (pre: 133 +/- 6 vs. post: 130 +/- 5 micromol ml(-1) min(-1), p = 0.375). In a matched inactive control group (n = 16) ADMA, MPO, cGMP levels and PON1 activity did not change over time. ADMA, MPO and cGMP changes were significantly different between participants and controls (all p < 0.05). Regular endurance exercise was successful in reducing the circulating levels of two promising cardiovascular risk markers, ADMA and MPO, in persons prone to cardiac events. These changes may result in numerous antiatherosclerotic effects such as improvement of NO bioavailability, reduction of oxidative stress and lipid peroxidation.