Interleukin (IL)-6 stimulates lipolysis in human and rodents adipocytes. However, the mechanism regulating this process is little known. In this study, we demonstrated that IL-6 increased lipolysis in differentiated porcine adipocytes by activation of extracellular signal-related kinase (ERK), which was inhibited by specific ERK inhibitor PD98059. IL-6 treatment did not elevate intracellular cAMP and specific PKA inhibitor H89 did not affect IL-6-induced lipolysis, which suggested that protein kinase A (PKA) pathway was not involved in IL-6-induced lipolysis. Also, the expressions of perilipin A and PPARγ2 were significantly reduced in response to IL-6 treatment, but the expressions of peroxisome proliferators-activated receptor gamma coactivator-1 alpha (PGC-1α), carnitinepalmitoyl-transferase-1 (CPT-1), and uncoupling protein 2 (UCP2) were significantly elevated. In conclusion, these results suggested that chronic high dose of IL-6 directly stimulated lipolysis in porcine adipocytes through activation of ERK, subsequently repressing perilipin A and promoting PGC-1α expression.