In Zucker obese rats (fa/fa) there are disturbances in the regulation of ACTH and corticosterone. In addition, β-endorphin concentrations are higher in the pituitary and hypothalamus in obese than in lean rats. Since ACTH and β-endorphin are thought to be controlled by corticotropin releasing factor (CRF), these effects may be due to abnormalities in CRF regulation. This possiblity was investigated by immunizing rats against CRF. Obese rats immunized against CRF developed higher titer antibodies than lean rats. Hypothalamic CRF concentrations were higher in CRF-immunized obese but not lean rats compared with those of control rats, suggesting that compensation for sequestration of peripheral CRF developed in obese rats. In obese, but not lean rats, immunization against CRF decreased weight gains during weeks 1–4 and increased gains during weeks 9–12 and food intakes were decreased during weeks 5–8 compared with those for obese rats immunized against bovine serum albumin (BSA). Adrenal glands weighed 30% less in both obese and lean rats immunized against CRF compared with those immunized against BSA. These responses to immunization against CRF occured even though plasma, hypothalamic and pituitary concentrations of ACTH and β-endorphin were unaffected at the end of the study.