Polypeptide from Chlamys farreri (PCF) is a novel marine polypeptide compound isolated from gonochoric Chinese scallop Chlamys farreri, this study we further investigate the mechanisms of PCF exerting its anti-apoptotic effect. The results indicated that PCF, ROS scavenger NAC and NF-kappaB inhibitor MG132 effectively inhibited UVB-induced HaCaT cells apoptosis. PCF (2.84mM) showed potential ROS scavenging activities in a kinetic process. PCF (1.42-5.69mM) dose-dependently increased the expressions of Cu, Zn-SOD, CAT and GPx meanwhile decreased the expressions of p-NF-kappaB/p65 and COX-2 in UVB-induced HaCaT cells. Additionally, pretreatment with NAC significantly declined the generation of ROS and the expression of p-NF-kappaB/p65. We concluded that ROS, NF-kappaB and COX-2 are involved in UVB-induced HaCaT cells apoptosis, PCF exerts its protective effects via scavenging ROS, increasing the expression of antioxidative enzymes and inhibition the activation of NF-kappaB and COX-2.