Electrolyte abnormalities are hallmark metabolic disturbances during the treatment of acute lymphoblastic leukemia (ALL). Hyponatremia is an ominous laboratory sign in the setting of neoplasia. We analyzed the incidence, risk factors, associations, specific interventions and outcomes of severe hyponatremia in a single-center series of children with ALL. The incidence of severe hyponatremia, defined as serum sodium levels below 130 mmol/L on at least 2 of 3 consecutive days, was 11.9%. History of hyponatremia episode is associated with neurologic complications (P=0.023) and the presence of overt central nervous system leukemia (CNS3) at diagnosis (P=0.005). Most observed hyponatremia episodes resolved relatively quickly, rarely requiring specific treatment. All but 1 hyponatremia episodes occurred in the induction or reinduction phases, but none before the administration of cytotoxic drugs, pointing to the role of therapy complications rather than leukemia per se. Most patients received vincristine shortly before hyponatremia onset, and vincristine has been previously strongly implicated in hyponatremia. We also suggest a role for imatinib. Although every patient with severe hyponatremia requires swift and thorough diagnostics a serious sequelae in the setting of pediatric ALL is rare. Hyponatremia association with neurotoxicity likely points to vincristine hypersensitivity in the subgroup of patients with both complications.