Cocaine- and amphetamine-regulated transcript is expressed in hypothalamic regions involved in the central control of food intake. Previous data have implicated cocaine- and amphetamine-regulated transcript as an anorectic peptide. We studied the effect of the active fragment of cocaine- and amphetamine-regulated transcript, cocaine- and amphetamine-regulated transcript-(55–102), on feeding when injected into discrete nuclei of the hypothalamus. Cocaine- and amphetamine-regulated transcript-(55–102) (0.04 nmol) elicited a delayed, but significant, increase in feeding in 24-h fasted rats after injection into the ventromedial nucleus (1–2 h, 261 ± 60% of control; P < 0.05) and arcuate nucleus (1–2 h, 225 ± 38% of control; P < 0.05) of the hypothalamus. Administration of a higher dose of cocaine- and amphetamine-regulated transcript-(55–102) (0.2 nmol) elicited a significant increase in feeding after injection into the ventromedial nucleus (1–2 h, 1253 ± 179% of control; P< 0.001), arcuate nucleus (1–2 h, 265 ± 43% of control; P < 0.05), paraventricular nucleus (2–4 h food intake, 186 ± 29% of control; P < 0.05), lateral hypothalamic area (2–4 h, 280 ± 34% of control; P < 0.001), anterior hypothalamic area (2–4 h, 252 ± 42% of control; P < 0.01), dorsomedial nucleus (2–4 h, 368 ± 29% of control;P < 0.001) and supraoptic nucleus (2–4 h, 212 ± 34% of control; P < 0.05) of the hypothalamus. Administration of cocaine- and amphetamine-regulated transcript-(55–102) into the third ventricle of the hypothalamus resulted in an inhibition in feeding [0–4 h (0.4 nmol), 33 ± 13% control; P < 0.001], but was associated with marked abnormalities in behavior, which may have interfered with feeding. These behavioral abnormalities were not observed after the administration of cocaine- and amphetamine-regulated transcript-(55–102) directly into the arcuate nucleus. These data suggest that cocaine- and amphetamine-regulated transcript may play an orexigenic role in the hypothalamic feeding circuitry.