OBJECTIVE The fate of inhaled nitric oxide (NO) has not been precisely defined in critically ill patients. This study aimed at defining the effects of long-term NO inhalation on circulating NO byproduct levels. METHODS During NO therapy, plasma and urine from 13 critically ill patients were sampled daily for determination of the stable byproducts of NO (nitrite [NO2-] and nitrate [NO3-]. Routine monitoring data included inhaled NO concentration, hemodynamic parameters, arterial blood gases, creatinine clearance, and C-reactive protein. RESULTS For the first 24 hours of NO inhalation (6.3+/-1.1 ppm), NO3- plasma concentration increased (from 13.3+/-5.4 to 52.3+/-17.6 micromol/L), but NO2- plasma concentration was not affected. The NO3- plasma concentration was correlated with the C-reactive protein level, the inhaled NO concentration. Renal excretion of NO metabolites was unaltered by NO inhalation. The NO3 concentrations returned to baseline when NO therapy was discontinued. CONCLUSIONS Long-term NO inhalation was associated with a consistent increase in the NO3- plasma concentration. NO byproducts may be implicated in the systemic effects associated with this treatment.