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Abstract: Objective: To investigate whether cytochalasin D-eluting stents (CDES) suppress intimal hyperplasia in porcine coronary arteries and to compare the efficacy of paclitaxel and cytochalasin D as inhibitors of vascular smooth muscle cell (SMC) proliferation and platelet aggregation in vitro. Methods: Rabbit platelet-rich plasma and SMC cultures derived from rabbit aortas were exposed to 10−8–10−5 M cytochalasin D or paclitaxel. Stents directly coated with 2 μg cytochalasin D (low-dose CDES, n =12) and bare stents (n =12) were randomly deployed in the right and left coronary artery of 12 pigs. Six weeks later, neointima was studied using quantitative coronary angiography (QCA) and morphometry. To examine a ten-fold higher dose, polybutyl methacrylate/polyvinyl acetate-coated stents were loaded with 20 μg cytochalasin D. High-dose CDES (n =10) and polymer-only stents (n =11) were deployed in 11 pigs. Results: After 7 days, cytochalasin D (IC50 9.9±0.4 10−8 M) and paclitaxel (IC50 1.1±0.4 10−8 M) inhibited SMC proliferation in vitro (n =4). In contrast, cytochalasin D (10−6–10−5 M, n =5), but not paclitaxel, attenuated platelet shape change and aggregation induced by ADP. In vivo QCA showed less late lumen loss in low-dose CDES (0.08±0.07 vs. 0.32±0.08 mm, P =0.05), but morphometry demonstrated only a tendency toward a decreased intimal area. High-dose CDES inhibited both late lumen loss (0.31±0.08 vs. 0.91±0.06 mm, P <0.01) and intimal area (1.57±0.20 vs. 2.46±0.22 mm2, P <0.01). Immunohistochemistry revealed that CDES suppressed peri-strut macrophage recruitment (CD68, P =0.04) and cell proliferation (Ki67, P =0.03) as compared to polymer-only stents without interfering with endothelial cell recovery or the density of α-SMC actin staining. Thromboses or edge effects were not observed in either study. Conclusions: CDES inhibited in-stent hyperplasia. The reduction (39%) with 20 μg CDES was equivalent to that reported for paclitaxel-eluting stents in pigs. Interference with platelet aggregation, SMC migration, SMC proliferation, and leukocyte recruitment could contribute to the benefit. The data indicate that targeting of actin microfilaments has a potential to suppress in-stent restenosis. [Copyright &y& Elsevier]