Increased fatty acid (FA) is often observed in highly proliferative tumors, contributing to promoting proliferation of tumor cells. FA affects secreted factors from tumor cells, which can modulate tumor microenvironment in favor of tumor survival. However, the secreted factors affected by the increased FA have not been systematically explored. Here, we performed comprehensive secretome profiling of oleate-treated and untreated HepG2 cells. Comparison of the secretomes identified 349 differentially secreted proteins (DSPs; 145 up-regulated and 192 down-regulated) in oleate-treated samples, compared to untreated samples. Functional enrichment and network analyses of the DSPs revealed that the 145 up-regulated secreted proteins by oleate treatment were mainly associated with cell proliferation-related processes, such as lipid metabolism, inflammatory response, and ER stress. Based on the network models of the DSPs, we selected four up-regulated secreted proteins (MIF, THBS1, PDIA3, and APOA1) that can represent such processes related to cell proliferation. Thus, our results provided a secretome profile indicative of oleate-induced proliferation of HepG2 cells.