The effect of surfactant administration for respiratory distress syndrome (RDS) on indomethacin (INDO) pharmacodynamics and dosing requirements for patent ductus arteriosus (PDA) closure and renal toxicity was evaluated. A 22-year prospective cohort study including 442 INDO-treated patients given 466 INDO treatment courses. The database included demographic information, medical problems, and medications. Neonates with a PDA confirmed by echocardiography were treated with INDO, 0.25-0.3 mg/kg. Subsequent INDO dosing was based on a combined pharmacokinetic/pharmacodynamic (PK/PD) approach. Data were fit to an Emax model and ANOVA was used to compare mean closure levels between groups. PDA closure was successful in 405 of 442 patients (91.6%) and in 434 of 466 treatment courses (93.1%) using an individualized PK/PD dosing approach. Renal toxicity was documented in 56 of 442 patients (12.7%) or 56 of 466 treatment courses (12.0%). Patients not treated with synthetic surfactant trended toward lower mean INDO concentrations at PDA closure compared to patients treated with synthetic surfactant (1.65 vs. 2.01 mg/l; P > 0.05) and significantly lower mean INDO concentrations at PDA closure compared to patients treated with natural surfactant (1.65 vs. 2.15 mg/l; P < 0.002). This requires an increased total dose of ~0.3 mg/kg or an individual dose increase of 0.1 mg/kg. Administration of natural or synthetic surfactant for RDS may increase the INDO concentrations and doses needed for PDA closure in premature infants.