We hypothesized that acute pharmacological blockade of cyclooxygenase-2 (COX-2) using nimesulide (Nime) would prevent maladaptive changes in left ventricular (LV) structure and function secondary to abdominal aortic coarctation-induced pressure overload (PO). In vivo LV chamber dimension and function were assessed by pressure/volume admittance catheter at 14 days' postsurgery in three groups (n ≥ 6/group): sham-operated (Sham); untreated PO; and selective COX-2 inhibitor nimesulide-treated PO (PO + Nime; 25 mg/kg/d). Treatment was initiated 24 h prior to surgical induction of PO. Relative to Sham, there was a marked increase in LV mass index in the PO groups (2.2 ± 0.01 mg/g versus 2.9 ± 0.10 mg/g Sham versus PO, PO+Nime: 2.5 ± 0.03 mg/g). End diastolic volume, an indicator of chamber size, was significantly decreased in the PO animals compared with Sham (202 ± 17μL versus 143 ± 16 μL Sham versus PO, PO + Nime: 226 ± 9 μL). Collagen levels in PO rats assessed by hydroxyproline analysis were significantly elevated relative to Sham values. Nimesulide treatment attenuated: (1) the increase in LV mass index; (2) the reduction in end diastolic volume; and (3) the PO-induced increase in myocardial collagen. In summary, acute COX-2 inhibition with nimesulide attenuated the maladaptive changes in the LV after PO. Acknowledging the clinical failure of chronic COX-2 inhibitor use, we propose that acute treatment with COX-2 inhibition during the initial stages of cardiac remodeling can be beneficial in maintaining the normal cardiac structure and function during PO.