The aim of this study was to test whether repetitive pretreatments of rats with ozonized oxygen at relatively low gas volumes into the abdomen (20 ml per rat per day) have any beneficial or detrimental effects on the course of a polymicrobial-induced lethal peritonitis. Peritonitis was induced in a surgical or a nonsurgical model by usage of fecal material from the cecum. As the biological read out we used the mortality analysis. To include possible mechanisms by which ozone might influence the septic outcome, we characterized the gene expression of the pro-inflammatory cytokines IL-1β, IL-2, and TNF-α mRNA in lymphoid organs. In both models, we found a significant beneficial influence of a dose-dependent O2/O3 pneumoperitoneum on the survival rate when compared to control animals or to room air. The ozone-enhanced survival seems to be independent from altered cytokine expression because there were no differences noticed in the levels of bacterial-induced gene expression of IL-1β and TNF-α in septic animals pretreated with ozonized oxygen when compared to control animals.