Efavirenz, used in treating pediatric human immunodeficiency virus infection, has central nervous system side effects. We report on a 5-year-old girl with perinatally acquired human immunodeficiency virus infection, presenting with new onset absence seizures after starting treatment with efavirenz. Plasma efavirenz values were above therapeutic range. The child was homozygous for the CYP2B6–516T/T genotype, which is associated with poor efavirenz clearance. Seizures abated after efavirenz discontinuation.