Many organs develop from epithelial-mesenchymal interactions such that in order to regenerate these organs, it might be a preferable strategy to recapitulate this process. However, in the current culture system designed for tissue interaction, the supplement of serum is required. The aim of this study is to explore the possibility of reproducing epithelial-mesenchymal interaction and ensuing morphogenesis in a serum-free condition. In accordance with the previous studies, by using a standard model of murine fetal submandibular gland (SMG), the tissue interaction and the morphogenesis were largely dependent on serum. Nonetheless, when tissue recombinants were cultivated on polyvinylidene fluoride (PVDF), but not on other biomaterials, the serum-deprived effect could be rescued. On PVDF, SMG tissue recombinant was able to increase epithelial size, de novo synthesize basement membrane, and develop new branches without serum. Although the gene expression levels of selected morphogens were not significantly altered, the precise localization of morphogenetic-decisive extracellular matrix such as type III collagen and the superior adsorbing capacity of essential diffusible factors like fibroblast growth factor 7 (FGF7) might account for PVDF effect. Accordingly, the result demonstrates that it is possible to establish a serum-free system that is competent in facilitating epithelial-mesenchymal interaction of salivary tissue. With PVDF, the crosstalk between SMG epithelia and mesenchyme could be sustained without serum.