Objective To investigate the effects of chronic multiplestress on learning and memory and on the levels of calcium/calmodulindependent protein kinase Ⅱ (CaMKⅡ), calmodulin (CaM) mRNA, and cAMPresponse element binding protein (CREB) mRNA in the hippocampus of rats and possible mechanisms. Methods The Wistar rats were divided randomly into stressed (n=16) and control groups (EM>n/EM>=16).The stressed group was given chronic multiplestress for 6 weeks to prepare the chronic multiplestressed model. The rats’ performance of spatial learning and memory was tested by Morris water maze (MWM) and Ymaze. The expressions of CaMKⅡ, CaM mRNA and CREB mRNA in hippocampus of rats’ were detected by immunohistochemistry, Western blotting and RT-PCR respectively. The width of synaptic cleft and the thickness of post-synaptic densities (PSD) were observed in the hippocampal CA3 region of rats under electron microscopy. Results After the exposure to chronic multiplestress for 6 weeks, the ability of learning and memory of the stressed group was higher than that of the control group (P<0.05, P<0.01). The width of synaptic cleft was 5.0580±1.4216 and the thickness of PSD was 20.9547±2.5693 in the hippocampal CA3 of stressed rats. Compared with the control group, the CaMKⅡ immunostaining of stressed animals was stronger in the stratum radiatum and oriens of hippocampal CA1 and CA3, especially in the stratum oriens. The expressions of CaMKⅡ, CaM mRNA, and CREB mRNA in the hippocampus of the stressed group was significantly higher (P&