The present study was undertaken to determine whether the severity of renal failure or hypertension in homozygous cyclooxygenase (COX)-2-deficient (COX-2−/−) mice affected by genetic background or gender. COX-2 deletion was introduced into three congenic genetic backgrounds, 129/Sv (129/COX-2−/−), C57/BL6 (C57/COX-2−/−), and BALB/c (BALB/COX-2−/−), by backcrossing the original mixed-background knockout mice with the respective inbred strains for 9 or 10 generations. Evaluation of the severity of hypertension and renal failure was performed in knockout and wild-type mice at the age of 2.5–3.5 mo. Blood pressure measured by tail-cuff plethysmography was significantly elevated in the male 129/COX-2−/− mice (165.8 ± 9.2 vs. 116 ± 5.1 mmHg, P < 0.05), and to a much lesser extent in the female 129/COX-2−/− mice (127.4 ± 3.3 vs. 102.4 ± 3.3), whereas it was unchanged in the C57- or BALB/COX-2−/− mice regardless of gender. Urinary excretion of albumin, determined by EIA, was remarkably increased in the 129/COX-2−/− (16.4 ± 4.1 vs. 0.16 ± 0.043 mg albumin/mg creatinine, P < 0.001), and to a lesser extent in the male C57/COX-2−/− mice (0.595 ± 0.416 vs. 0.068 ± 0.019). Albumin excretion was not elevated in the male BALB/COX-2−/− or in female COX-2−/− mice on any of the three genetic backgrounds. Histological analysis showed abundant protein casts, dilated tubules, and infiltration of inflammatory cells in the male 129/COX-2−/− mice, but not in COX-2−/− mice in other strains or gender. However, the presence of small glomeruli in the nephrogenic zone was observed in all strains of COX-2 knockout mice, regardless of genetic background and gender. Therefore, we conclude that the severity of hypertension and renal failure in COX-2-deficient mice is influenced by genetic background and gender, whereas the incomplete maturation of outer cortical nephrons appears to be independent of genetic background effects.