Perfluorooctanesulfonate (PFOS) is an environmental contaminant found in human and animal tissues worldwide. The developing nervous system is thought to be particularly sensitive to PFOS by the fact that PFOS can cross blood-brain and placental barriers. Effect of gestational and lactational exposure to PFOS on central nervous system (CNS) in Wistar rats was investigated by the cross-foster model built with PFOS at 0 or 3.2 mg/kg food. Real-time reverse transcription-polymerase chain reaction was employed to evaluate the gene expression of calcium-dependent signaling molecules in rats' hippocampus which are critical to the function of CNS. The expression of calcium-related signaling molecules, such as N-methyl-D-aspartate receptor subtype-2B (NR2B), calmodulin (CaM), Ca2+/calmodulin-dependent kinase II alpha (CaMKIIalpha) and cAMP-response element-binding (CREB) were increased in the PFOS exposure group at postnatal day 1 (PND 1). The decreased NR2B in the prenatal PFOS exposure group, the decreased CaM in the pre-/postnatal PFOS exposure group, the increased CaMKIIalpha in the whole-life PFOS exposure group and the increased CREB in the prenatal/whole-life PFOS exposure group was observed at PND 7. At PND 35, rats exhibited the decreased NR2B in the pre-/postnatal and the whole-life PFOS exposure group, and the decreased CaM in the postnatal PFOS group. The results indicate that perinatal exposure to PFOS during the critical period of development of the brain may have neurotoxic effect on CNS by mediating the molecules of calcium signaling pathway.