The cytokine tumor necrosis factor (TNF)-α has been causally linked to left ventricular (LV) remodeling, but the molecular basis for this effect is unknown. Matrix metalloproteinases (MMPs) have been implicated in cardiac remodeling and can be regulated by TNF-α. This study tested the central hypothesis that administration of a TNF-α blocking protein would prevent the induction of MMPs and alter the course of myocardial remodeling in developing LV failure. Adult dogs were randomly assigned to the following groups: 1) chronic pacing (250 beats/min, 28 days, n = 12), 2) chronic pacing with concomitant administration of a TNF-α blocking protein (TNF block) using a soluble p75 TNF receptor fusion protein (TNFR:Fc; administered at 0.5 mg/kg twice a week subcutaneously,n = 7), and 3) normal controls (n = 10). LV end-diastolic volume increased from control with chronic pacing (83 ± 12 vs. 118 ± 10 ml,P < 0.05) and was reduced with TNF block (97 ± 9 ml, P < 0.05). MMP zymographic levels (92 kDa, pixels) increased from control with chronic pacing (36,848 ± 9,593 vs. 87,247 ± 12,912, P < 0.05) and was normalized by TNF block. Myocardial MMP-9 and MMP-13 levels by immunoblot increased with chronic pacing relative to controls (130 ± 10% and 118 ± 6%, P < 0.05) and was normalized by TNF block. These results provide evidence to suggest that TNF-α contributes to the myocardial remodeling process in evolving heart failure through the local induction of specific MMPs.