Background: Sex difference was reported to affect both the process of nephrotoxicity induced by Cisplatin and the different protectant strategies. Nigella sativa seed and oil exhibited antioxidant and anti-inflammatory properties with proven protection against Cisplatin-induced nephrotoxicity in male rats. work aimed to clarify the role of sex difference in Cisplatin-induced nephrotoxicity, and the possible sex-related nephroprotective effect of Nigella s. oil. Material and Methods: The study included thirty-six adult albino rats (18 males and 18 females). Rats were randomly classified into 6 groups, 3 groups for each sex, group 1&2: control groups; group 3&4: each rat in these groups received a single dose of 6 mg/kg Body weight (BW) Cisplatin injection on the 6th day; and group 5&6: each rat in these groups received 2 ml/kg BW Nigella s. oil orally for 11 consecutive days and a single dose of 6 mg/kg BW Cisplatin injection. The rats were sacrificed on the 12th day. Serum creatinine and urea concentrations were estimated. 2 Histopathological procedures using Hx & E, Masson’s Trichrome, and PAS stains and immunohistochemical procedures using NFκB P65 and PPARγ antibodies were done for kidney sections. Results: Cisplatin treatment induced significant body weight loss, significant increase of normalized kidney weight, significant elevation of serum creatinine and serum urea levels, histopathological changes of kidney tissues, marked increase of NFκB-P65 antibody expression within the renal tubular cells, and marked decrease of PPARγ antibody expression in the nuclei of renal tubular cells for both sexes, but male rats were significantly more affected than female rats. Nigella s. oil has ameliorated all the above changes in both sexes without sexual dimorphism. Conclusion: Female rats were more resistant to nephrotoxicity induced by Cisplatin, while Nigella s. oil has ameliorated cisplatin-induced nephrotoxicity for both male and female rats without apparent sexual dimorphism.