Past experience with the disposition of procainamide hydrochloride (PA) in neonates is restricted to a single case study involving placental transfer. We studied aspects of PA pharmacokinetics in three neonates who received constant-rate infusion therapy. Results indicated that the total serum clearance of PA is similar to the adult value, but elimination half-lives of both PA and N-acetylprocainamide (NAPA) were slightly prolonged and volume of distribution was variable. Pharmacokinetic evaluations in a renally compromised neonate confirmed that total PA clearance and the renal clearance of both PA and NAPA were reduced, although not to the extent expected for the degree of renal impairment. Peritoneal dialysis was used concurrently and may have contributed to the elimination process. We believe that our experience provides important preliminary guidelines for the management of PA therapy in neonates.