Background: Capsular contracture remains a major problem following prosthetic breast implantation, especially in patients undergoing irradiation. Recent studies suggest that such radiation injuries are a cascading process of cytokine activation, with transforming growth factor (TGF)-β acting as the "master switch." Because TGF-β signals through phosphorylation of Smad3, a plausible approach to abate TGF-β-induced capsular contracture would be to interrupt Smad3 signaling. To test this hypothesis, capsular contracture formation in wild-type and Smad3 knockout mice was compared using micro-computed tomographic and histologic examination. Methods: On day 0, 48 mice were implanted with bilateral silicone gel implants. Postoperatively, animals were imaged using live-scan micro-computed tomographic scanning. Animals in the radiation arm then received a 10-Gy directed radiation dose. On postoperative days 21, 28, 35, and 42, animals were imaged again. Histologic evaluation was performed at necropsy. Results: Irradiated implants in the wild-type mice demonstrated shape and contour deformation on micro-computed tomographic scanning beginning on postoperative day 21 and progressing through day 42. Conversely, micro-computed tomographic scanning of irradiated implants in knockout mice demonstrated few changes from day 0 through day 42. Corresponding histologic specimens from wild-type mice demonstrated irregular capsules composed of disorganized collagen that became thicker from day 21 to day 42. Irradiated knockout specimen maintained thin capsules from day 21 through day 42. Conclusions: In this work, inhibiting TGF-β signaling led to a reduction in radiation-induced capsular contracture as measured by micro-computed tomographic and histologic evaluation. The results of this study suggest a promising target for the prevention of capsular contracture through the development of anti-Smad3/TGF-β-based therapies.