Infant respiratory distress syndrome (RDS) involves inflammatory processes, causing an increased expression of inducible heme oxygenase with subsequent production of carbon monoxide (CO). We hypothesized that increased production of CO during RDS might be responsible for increased plasma levels of vasodilatory cyclic guanosine monophosphate (cGMP) and, consequently, low blood pressure observed in infants with RDS. Fifty-two infants (no-RDS, n= 21; RDS, n= 31), consecutively admitted to the NICU between January 2003 and October 2003 were included. Hemoglobin-bound carbon monoxide (COHbc), plasma cGMP, plasma nitric oxide (NOx) and bilirubin were determined at 0-12, 48-72, and at 168 hours postnatally, with simultaneous registration of arterial blood pressure. Infants with RDS had higher levels of cGMP and COHbc as compared to no-RDS infants (RDS vs no-RDS: cGMP ranging from 76 to 101 vs 58 to 82 nmol/L; COHbc ranging from 1.2 to 1.4 vs 0.9 to 1.0%). Highest values were reached at 48-72 h (RDS vs no-RDS [mean + SD]: cGMP 100 + 39 vs 82 + 25 nmol/L [p < 0.001]; COHbc 1.38 + 0.46 vs 0.91 + 0.26% [p < 0.0001]). Arterial blood pressure was lower and more blood pressure support was needed in RDS-infants at that point of time (RDS vs no-RDS [mean + SD]: MABP 33 + 6 vs 42 + 5 mmHg [p < 0.05]). NOx was not different between groups and did not vary with time. Multiple linear regression analysis showed a significant correlation between cGMP and COHbc, suggesting a causal relationship. Mean arterial blood pressure appeared to be primarily correlated to cGMP levels (p < 0.001). We conclude that a CO-mediated increase in cGMP causes systemic vasodilation with a consequent lower blood pressure and increased need for blood pressure support in preterm infants with RDS.