Carcinoma-associated fibroblasts (CAFs) have been confirmed to play an important role in the occurrence and development of many kinds of tumors. Regarding proliferation as one manifestation of malignance, the objective was to observe the effects of oral CAFs on the proliferation of oral squamous carcinoma cells (OSCC) and to explore the role of keratinocyte growth factor (KGF) in this process. The results showed that oral CAFs secreted a higher level of KGF than oral normal fibroblasts (NFs), and the conditioned medium of CAFs could increase the viability of carcinoma cells and promote more of them into G2 and S phase. However, after blocking with KGF antibody, the viability and cell cycle of Tca8113 cultured with CAFs conditioned medium changed to be similar with NFs control groups. It was concluded that CAFs could promote the proliferation of OSCC through secreting high levels of KGF. These findings support the use of carcinoma-associated fibroblasts as a novel target in anticancer therapy.