Flaxseed derivatives, including both oil and flax lignan, modify progression of renal injury in animal models, including Han:SPRD-cy polycystic kidney disease (PKD). Gender is a significant factor in the rates of progression of many forms of human renal disease, but the role of gender in the response to nutrition intervention in renal disease is unexplored. In this study, male and female Han:SPRD-cy rats or normal littermates were fed either corn oil (CO) or flax oil (FO) diets, with or without 20 mg/kg of the diet flax lignan secoisolaricinoresinol dyglycoside (SDG). Renal injury was assessed morphometrically and biochemically. Renal and hepatic PUFA composition was assessed by GC and renal PGE2 release by ELISA. FO preserved body weight in PKD males, with no effect in females. SDG reduced weight in both normal and PKD females. FO reduced proteinuria in both male and female PKD. FO reduced cystic change and renal inflammation in PKD males but reduced cystic change, fibrosis, renal inflammation, tissue lipid peroxides, and epithelial proliferation in PKD females. SDG reduced renal inflammation in all animals and lipid peroxides in PKD females. A strong interaction between SDG and FO was observed in renal FA composition of female kidneys only, suggesting increased conversion of C18 PUFA to C20 PUFA. FO reduced renal release of PGE2 in both genders. Gender influences the effects of flaxseed derivatives in Han:SPRD-cy rats. Gender-based responses to environmental factors, such as dietary lipid sources and micronutrients, may contribute to gender-based differences in disease progression rates.