Cardiac remodeling is a determinant of the clinical progression of heart failure and now slowing or reversing remodeling is considered as a potential therapeutic target in heart failure. Pycnogenol® has been reported to mediate a number of beneficial effects in the cardiovascular system but its effects on hemodynamic and functional cardiovascular changes following cardiac remodeling have not been elucidated. Therefore, we investigated the influence of Pycnogenol® supplementation (30 mg/kg) on left ventricular function and myocardial extracellular matrix composition in old C57BL/6N mice following induction of cardiac remodeling by chronic nitric oxide synthase blockade by NG-nitro-L: -arginine methyl ester (L: -NAME) administration. L: -NAME-treated mice demonstrated dilated cardiomyopathy at compensated state, associated with a significant increase of pro-matrix metalloproteinase (MMP)-9 gene expression and activity, a marked decrease in pro-collagen IIIα1 gene expression, and a subsequent reduction in cardiac total and cross-linked collagen content. Upon supplementation with Pycnogenol® in L: -NAME-exposed mice, cardiac gene expression patterns for pro-MMP-2, -9, and -13, and MMP-9 activity were significantly decreased, associated with a significant increase in cardiac tissue inhibitor of metalloproteinase (TIMP)-4 expression. These findings were coincided with a marked increase in myocardial total and cross-linked collagen content, compared with L: -NAME-only-treated mice. Moreover, Pycnogenol® treatment was associated with reversal of L: -NAME-induced alternations in hemodynamic parameters. These data indicate that Pycnogenol® can prevent adverse myocardial remodeling induced by L: -NAME, through modulating TIMP and MMPs gene expression, MMPs activity, and further reduction in myocardial collagen degradation rate.