Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (OMIM 238970) is an autosomal recessive disorder that is caused by a deficiency of mitochondrial ornithine transporter 1, resulting in dysfunction of the urea cycle. HHH is the rarest of the urea cycle disorders, reported in fewer than 100 patients. It is characterized by extreme phenotypic variability, including diverse ages of onset and severity of phenotype. We report the first confirmed instance of HHH syndrome in a premature infant (31 2/7 weeks) with severe hyperammonemia (1,300 μmol/L).This case highlights the importance of considering HHH in the differential diagnosis for neonatal hyperammonemia. Because HHH is not detected by newborn screening, and the characteristic biochemical triad may be subtle or even absent, it has the potential to be underdiagnosed; however, making the diagnosis has critical therapeutic implications as treatment is distinct from other urea cycle defects. For instance, lysine supplementation is a beneficial treatment unique to HHH. Therefore, we present here a review of previously reported cases in order to demonstrate the full spectrum of the disease and highlight potentially diagnostic features.