We reviewed clinical data in 33 patients with transient hyperammonemia of the newborn (THAN): six previously unreported cases and 27 from the literature. Thirteen neonates with urea cycle enzyme deficiencies (UCED) served for comparison. No differences were found in the incidence of perinatal complications, route of delivery, Apgar scores, sex, or incidence or time of onset of seizures. On the other hand, neonates with THAN had significantly lower birth weights (mean +/- SEM 2282 +/- 78 gm vs 3336 +/- 222 gm, P less than 0.001) and gestational ages (35.1 +/- 0.5 weeks vs 39.6 +/- 0.5 weeks, P less than 0.001). Mean time of onset of respiratory distress (3.9 +/- 1.4 hours vs 71.5 +/- 26.1 hours, P less than 0.001), ventilatory support (P less than 0.001), lethargy (P less than 0.005), and coma (P less than 0.005) occurred earlier in THAN. Distinctive laboratory findings in patients with THAN included abnormal chest radiographic findings and plasma ammonium concentrations that were higher (1871 +/- 209 microM vs 973 +/- 169 microM, P less than 0.02) at an earlier age. Respiratory distress occurred in all but one patient with THAN before 24 hours; in contrast, only 62% of infants with UCED had respiratory symptoms, and none before 30 hours. In this retrospective study, the clinical presentation alone differentiated THAN from UCED.