Lead exposure has been associated with increased cardiovascular risk, which may result, at least in part, from lead-induced increases in oxidative stress and depressed nitric oxide (NO) availability. However, no previous clinical study has examined whether lead exposure is associated with significant effects on biomarkers of NO activity (plasma nitrites, nitrates, and cyclic guanosine 3',5'-monophosphate; cGMP). We investigated whether there is an association between the circulating concentrations of nitrites, nitrates, and cGMP and the concentrations of lead in whole blood (B-Pb) or plasma (P-Pb) from 62 lead-exposed subjects (30 men and 32 women). P-Pb was determined by inductively coupled plasma mass spectrometry and B-Pb by graphite furnace atomic absorption spectrometry. Plasma nitrite and nitrate concentrations were measured using an ozone-based chemiluminescence assay. Plasma cGMP concentrations were measured using a commercial enzyme immunoassay. We found a negative correlation between plasma nitrite and B-Pb concentrations (r = -0.358; P = 0.004), and between plasma nitrite and P-Pb concentrations (r = -0.264; P = 0.038), thus suggesting increased inhibition of NO formation with increasing B-Pb or P-Pb concentrations. However, no significant correlations were found between plasma nitrate or cGMP and B-Pb or P-Pb concentrations (all P > 0.05). These findings suggest a significant inhibitory effect of lead exposure on NO formation and provide clinical evidence for a biological mechanism possibly involved the association between lead exposure and increased cardiovascular risk.