To measure serum monocyte chemotactic protein-1 (MCP-1) in patients with congenital diaphragmatic hernia (CDH) and investigate its relationship to the development of persistent pulmonary hypertension (PPH). Serum MCP-1 was measured in 13 neonates with high risk for CDH at the time of diagnosis and postoperatively, and in five age-matched controls using an ELISA system. The 13 CDH subjects were divided into four groups according to the presence of PPH and outcome. Group I (severe-pre group): subjects with severe PPH who died prior to surgery (n = 5); Group II (mild-pre group): subjects with mild PPH controlled by medications (n = 8); Group IIa (severe-post group): subjects who subsequently developed severe PPH postoperatively and died (n = 3); and Group IIb (mild-post group): subjects who continued to have mild PPH controlled by medications. We also examined nitrofen-induced hypoplastic lungs from five rat fetuses with CDH and five control lung specimens for MCP-1 using immunohistochemistry. Mean serum MCP-1 in Group I was (1038.0 +/- 95.8 pg/ml), which was significantly higher than Group II (444.9 +/- 39.7 pg/ml) (P < 0.0001) and controls (147.3 +/- 11.3 pg/ml) (P < 0.0001). Postoperatively, Group IIa was significantly higher than Group IIb from 24 to 120 h postoperatively (P < 0.001). In Group IIb serum MCP-1 did not rise at all between 24 and 120 h postoperatively. Hypoplastic fetal rat CDH lungs had strong expression of MCP-1 compared with control lungs. Up-regulated expression and high circulating levels of MCP-1 in CDH patients with PPH suggest that MCP-1 may play a role in the development of PPH in CDH.