Cyclosporin A (CsA) inhibits collagen remodeling by interfering with the collagen binding step of phagocytosis. In rapidly remodeling connective tissues such as human periodontium this interference manifests as marked tissue overgrowth and loss of function. Previous data have shown that CsA inhibits integrin-induced release of Ca²⁺ from internal stores, which is required for the binding step of collagen phagocytosis. As gelsolin is a Ca²⁺-dependent actin severing protein that mediates collagen phagocytosis, we determined if gelsolin is a CsA target. Compared to vehicle controls, CsA-treatment of wild-type mice increased collagen accumulation by 60% in periodontal tissues; equivalent increases were seen in vehicle-treated gelsolin-null mice. Collagen degradation by phagocytosis in cultured gelsolin wild-type fibroblasts was blocked by CsA, comparable to levels of vehicle-treated gelsolin null fibroblasts. In wild-type cells treated with CsA, collagen binding was similar to that of gelsolin-null fibroblasts transfected with a gelsolin severing mutant and treated with vehicle. CsA blocked collagen-induced Ca²⁺ fluxes subjacent to bound collagen beads, gelsolin recruitment and actin assembly at bead sites. CsA reduced gelsolin-dependent severing of actin in wild-type cells to similar levels as gelsolin-null fibroblasts. We conclude that CsA-induced accumulation of collagen in the extracellular matrix involves disrupting the actin severing properties of gelsolin, thereby inhibiting the binding step of collagen phagocytosis.