Objectives: Here we have evaluated the effects of a combination of antioxidants (N-acetylcysteine plus deferoxamine) in cognitive deficit and the oxidative damage in the hippocampus of severe sepsis survivors rats. Methods: Male Wistar rats (300-350g) subjected to CLP were treated vehicle with “basic support” (saline at 30 mL/kg 3 and 12 hs after CLP, ceftriaxone at 30 mg/kg and clindamycin at 25 mg/kg every 12 and 8 hs, respectively, up to 48 hs), vehicle with basic support and   N-acetylcysteine (20 mg/kg, 3 hrs, 6 hrs, 12 hrs, 18 hrs, and 24 hrs after CLP, subcutaneously) or deferoxamine (20 mg/kg, 3 hrs and 24 hrs after CLP, subcutaneously) or  both N-acetylcysteine plus deferoxamine as described above. Sham group received vehicle and basic support.  Ten or 30 days aftre CLP, survivors rats were eparately submitted to 3 classical behavioral tasks to evaluate learning and memory: inhibitory avoidance task (IA), continuous multiple-trials step-down inhibitory avoidance task (CMSIA) and habituation to an open-field (OP). The oxidative damage, assessed by the thiobarbituric acid reactive species (TBARS) and the protein carbonyl assays, were performed in the hippocampus 6 hs after surgerical procedures. Results: In the IA, all groups presented an aversive memory impairmente compared to sham group, except the group treated with basic support and NAC pus DFX, in which, there were not significant difference compared to sham.  The same results were observed in the CMSIA learning performance. In the OP, only basic support and NAC plus DFX treatment prevent habituation memory impairment observed in all other groups compared to sham. These results were observed in both 10 and 30 days after CLP. In accordance to behavioral outcomes, we found that hippocampus were protected against oxidative damage only in the basic support and NAC plus DFX treatment, in both parameters assessed. Conclusions: Our data provide the first experimental domonstration that N-acetylcysteine plus deferoxamine prevent short- and long-term cognitive impairment in survivors rats from CLP-induced sepsis, suggesting a major role of oxidative stress in late cognitive impairment in sepsis survivors. These, together with our previous results, demonstrated that besides a positive effect upon mortality, NAC plus DFX could attenuate late sequelae observed in sepsis survivors.