Cranial irradiation with or without chemotherapy can cause hypothalamic-pituitary dysfunction. Chemotherapy without cranial irradiation has not been thought to cause such deficiency. In order to determine whether chemotherapy without cranial irradiation can lead to hormonal deficiency, we reviewed the medical records of 362 childhood cancer patients who underwent full hypothalamic-pituitary evaluation because of altered growth and development after oncological therapy (1987-2002). Of these, 31 received chemotherapy but no cranial or total body irradiation and had no CNS tumor: 18 had hematological malignancy and 13 had a solid tumor of the torso or extremity. Duration of follow-up was 13.0 +/- 4.1 years (mean +/- SD). Growth hormone deficiency (GHD) was identified in 15 (48%), central hypothyroidism (TSH-D) in 16 (52%), and pubertal abnormalities in 10 (32%). Pubertal abnormalities included precocious puberty in two (6%), gonadal failure in five of 27 who were old enough to assess puberty (19%), and gonadotropin deficiency in three of 27 (11%). GHD and TSH-D were co-existent in eight patients (26%). Overall, 81% (n = 25) had GHD, TSH-D, precocious puberty, and/or gonadotropin deficiency. None had ACTH or ADH deficiency or primary hypothyroidism. Of note, this was not a study of prevalence, but rather an evaluation of clinically referred patients. In conclusion, hypothalamic dysfunction may occur in survivors of non-CNS tumors who receive chemotherapy but do not receive cranial irradiation. We recommend at least annual observation of growth rate and pubertal development of all children treated for pediatric malignancies, with evaluation for GHD, TSH-D, pubertal abnormalities, and other hypothalamic dysfunction in all poorly-growing cancer survivors, even those not treated with cranial irradiation.