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Silk ribroin (SF)-based or -coated biomaterials are likely to be endowed with properties fitting tissue engineering applications. In this work we investigated the interactions between SF-coated polyurethane (PU) membranes and foams, and four different strains of normal human adult fibroblasts (HAF). In parallel, the same cell strains were grown on polystyrene plates and uncoated PU scaffolds. With respect to the uncoated homologues, cell adhesion to SF-coated PU membranes was two-fold within 3 h and cell numbers were 2.5-fold higher after 30 days in culture; SF-coated PU foams were found to harbor 1.39-fold more cells after 30 days in vitro (p < 0.01). This enhanced cell growth was coupled with a more intense uptake of glucose and a higher secretion rate of lactate, but with similar consumption of glutamine. In addition, cells on SF-coated membranes exhibited a higher secretion rate of interleukin-6. HAF cultured on all types of substrates were never found to secrete any ELISA-assayable amount of the main pro-inflammatory cytokines IL-1β, TNF-α, and TGF-β1. The rate of the extracellular assembly of collagen type I fibers, measured by the release of procollagen C-peptide, was found to be somewhat higher on both 2D and 3D SF-coated PU scaffolds. On the whole, these results show that SF-coated PU substrates constitute a novel type of composite biomaterial that promotes cell adhesion and growth, and the performance of specific metabolic tasks of normal HAF without inducing any secretion of some of the most relevant proinflammatory cytokines.