Hypoxic mice had a higher BV index compared with normoxic mice (mean BV index, 0.0059 vs 0.0040, respectively; p < 0.01). HO-1 null mice responded to chronic hypoxia with a significantly higher BV index compared with hypoxic wild-type mice (0.0068 vs 0.0059, respectively; p < 0.05), but HO-1 null mice treated with biliverdin were protected from this increase (untreated mice, 0.0068; biliverdin-treated mice, 0.0059; p < 0.01). CO treatment had no effect on the BV index of HO-1 null mice or wild-type mice. Masson trichrome staining showed that while none of the wild-type mice developed fibrosis of the RV wall, 5 of 11 HO-1 null mice that had been exposed to hypoxia alone and 9 of 14 HO-1 null mice that were exposed to hypoxia plus CO developed wall fibrosis. In contrast, none of the biliverdin-treated HO-1 null mice developed fibrosis. In all mice exposed to hypoxia, regardless of genotype, inhaled CO reduced pulmonary arteriolar vascular wall thickness to levels similar to normoxic animals (mean percentage wall thickness: hypoxia, 28%; hypoxia + CO, 24%; normoxia, 22%; p < 0.05 [for hypoxia group vs other groups]). In contrast, biliverdin treatment had no effect on pulmonary arteriolar wall thickness.