To evaluate the impact of sleep deprivation (SD) on microbially induced alterations in sleep, we used gentle handling to deprive rabbits of sleep for 4 h before or after intravenous inoculation with Escherichia coli (EC). Sleep was monitored for the next 20 h. EC inoculation alone increased slow-wave sleep (SWS) time, delta-wave amplitude (DWA) during sleep and SWS bout length during the initial 2-4 h after inoculation. During the following 8-20 h, DWA during SWS was reduced relative to control values. SD alone increased SWS time and SWS bout length for 2 h after the end of the SD period. Rabbits subjected to SD for 4 h prior to EC inoculation demonstrated increases in SWS time, DWA during SWS and SWS bout length 2-4 h postinoculation. At some time points, these effects were greater in magnitude than those induced by either manipulation alone, but they were generally equivalent to the additive effects of the individual treatments. Rabbits subjected to SD after EC inoculation (i.e. during the period in which EC increases sleep) demonstrated increases in SWS time and DWA during SWS for only 2 h after the end of the SD period, suggesting that these animals maintained a sleep deficit as compared to rabbits inoculated with EC alone. SD alone elicited hyperthermia in rabbits, and EC-inoculated rabbits subjected to SD developed fevers greater than those induced by either treatment alone. Other clinical indices were not significantly affected by the combined treatments. These data indicate that the sleep changes that occur subsequent to bacterial inoculation are altered in sleep-deprived rabbits, but that SD does not exacerbate clinical illness in this model.