Although prolactin is reported to counteract the immunosuppressive effects of glucocorticoids, cyclosporine, and morphine, it remains unknown whether prolactin has any salutary effects on the depressed immune responses following severe hemorrhage. To study this, mice were bled to and maintained at a mean arterial pressure of 35 mm Hg for 60 min, then adequately resuscitated and divided into two groups. One group received saline vehicle, while the other group received prolactin (100 μg/25 g body weight, s.c.) immediately before resuscitation. Two hours thereafter, peritoneal (pMφ) and splenic macrophages (sMφ) were harvested and assessed not only for their ability to release IL-1 and IL-6, but also for cytokine gene expression using semiquantitative reverse transcription and PCR. In an additional group, mice were subjected to sepsis by cecal ligation and puncture 3 days after hemorrhage. Hemorrhage markedly decreased the ability of pMφ and sMφ to release IL-1 and IL-6. This was, however, associated with increased mRNA expression for IL-1β and IL-6 and increased serum corticosterone levels. Following prolactin treatment of hemorrhaged mice, IL-1β and IL-6 mRNA levels as well as cytokine release capacity and blood corticosterone levels were comparable to the values in sham animals. Prolactin also improved the survival of animals subjected to sepsis after hemorrhage. Thus, the immunosuppression following hemorrhage appears to be mediated and modulated by hormones from the hypothalamic-pituitary-adrenal axis. Furthermore, prolactin represents a novel immunomodulating hormone for the treatment of immunodepression encountered after hemorrhagic shock and for decreasing the mortality from subsequent sepsis under those conditions.