Abstract OBJECTIVES Intima hyperplasia is a major issue of biological cardiovascular grafts resulting in progressive in vivo degeneration that particularly decreases the durability of coronary and peripheral vascular bypasses. Previously, dichloroacetate (DCA) has been reported to prevent the formation of hyperplastic intima in injured arteries. In this study, the effect of DCA on the neointima formation and degeneration of decellularized small-caliber implants was investigated in a rat model. METHODS Donor rat aortic grafts (n = 22) were decellularized by a detergent-based technique, surface-coated with fibronectin (50 µl ml−1, 24 h incubation) and implanted via anastomoses to the infrarenal aorta of the recipients. Rats in the DCA group (n = 12) received DCA via drinking water during the whole follow-up period (0.75 g l−1), while rats without DCA treatment served as controls (n = 10). At 2 (n = 6 + 5) and 8 (n = 6 + 5) weeks, the grafts were explanted and examined by histology and immunofluorescence. RESULTS Systemic DCA treatment inhibited neointima hyperplasia, resulting in a significantly reduced intima-to-media ratio (median 0.78 [interquartile range, 0.51–1.27] vs 1.49 [0.67–2.39] without DCA, P < 0.001). At 8 weeks, neointima calcification, as assessed by an established von Kossa staining-based score, was significantly decreased in the DCA group (0 [0–0.25] vs 0.63 [0.06–1.44] without DCA, P < 0.001). At 8 weeks, explanted grafts in both groups were luminally completely covered by an endothelial cell layer. In both groups, inflammatory cell markers (CD3, CD68) proved negative. CONCLUSIONS Systemic DCA treatment reduces adverse neointima hyperplasia in decellularized small-caliber arterial grafts, while allowing for rapid re-endothelialization. Furthermore, DCA inhibits calcification of the implants.