In this study, the effects of (1) asphyxia and (2) asphyxiation followed by resuscitation on brain levels of prostaglandins E2 and F2 alpha were evaluated in 2-day-old guinea pigs. Asphyxiation in a nitrogen atmosphere for either 3 min or 3 min 40 s did not alter brain PGF2 alpha levels but after 3 min 40 s of asphyxia, brain PGE2 levels were significantly elevated from control values. When asphyxiation was followed by resuscitation with 95% O2 and 5% CO2, brain PGF2 alpha levels rose significantly while PGE2 levels were not different from nonasphyxiated control values. Pretreatment of animals with indomethacin lowered brain levels of both prostaglandins below nonasphyxiated control levels and prevented any asphyxiation or resuscitation-induced rise in brain prostaglandin levels. Also, animals which were asphyxiated, resuscitated, and sacrificed 1 day after asphyxiation had brain prostaglandin levels which were not different from levels in nonasphyxiated control animals. These studies demonstrate a significant rise in brain PGF2 alpha levels following resuscitation from acute total asphyxia. We speculate that the resuscitation-induced rise in brain PGF2 alpha may contribute to restriction of cerebral blood flow in the postasphyxial period through its action as a vasoconstrictive agent.