Guinea pig pups vocalized and ambulated when first isolated in a test cage; at 1 and 24 hr, levels of these behaviors had waned, and pups frequently exhibited a crouched stance, eye-closing, and piloerection. Injection (s.c.) of corticotropin-releasing factor (CRF) prior to isolation diminished the initial vocalization and locomotor responses and induced pups to exhibit the crouched stance, eye-closing, and piloerection at the beginning of the isolation period. Pretreatment with a CRF-receptor antagonist reversed the behavioral effects of CRF. CRF had no effect on blood pressure. Thus, s.c. CRF produced the same behavioral profile as seen with the passage of time in untreated isolated pups. The behavioral effects appeared to be CRF-receptor-mediated events and were not secondary to hypotension. These results support the hypothesis that during prolonged isolation, high or sustained peripheral CRF activity modulates behavior.