Renal oxidative stress is increased in response to ureteral obstruction. In vitro, cyclooxygenase-2 (COX-2) activity contributes to protection against oxidants. Here, we test the hypothesis that COX-2 activity counters oxidative stress and apoptosis in an in vivo model of obstructive nephropathy. Renal oxidative stress markers, antioxidant enzymes and markers of tubular injury, tubular dilation and apoptosis were investigated in COX-2 knockout (COX-2^-/-) and wild type (WT) mice subjected to 3 or 7 days of unilateral ureteral obstruction (UUO). In a separate series, sham and UUO WT mice were treated with a selective COX-2 inhibitor, parecoxib. COX-2 increased in response to UUO; oxidative stress markers 4-hydroxynonenal (4-HNE) and nitrotyrosine protein residues increased in kidney tissue with no genotype difference after UUO while antioxidant enzymes Heme oxygenase-1 (HO-1) and superoxide dismutases (SOD2) displayed higher levels in COX-2-/-. Tubular injury was aggravated by COX-2 deletion as measured by tubular dilatation, KIM-1 increase, cortical caspase-3 content and apoptosis index. In conclusion, COX-2 is necessary to protect against tubular injury and apoptosis after UUO but not necessary to protect against oxidative stress. COX-2 is not likely to directly regulate antioxidant enzymes HO-1 and SOD in the kidney.