Objective To investigate the role of P2X7 receptor in learning and memory dysfunction induced by HIV-1 enveloped protein gp120 in rats. Methods The imitating HIV-1 associated dementia (HAD) animal models were established by intracerebroventricular (ICV) infusion of gp120 in rats. The effect of gp120 on the learning and memory dysfunction in rats was evaluated by Morris water maze (MWM) test. The role of P2X7 receptor (P2X7R) was studied by Western blot and PCR assay. Results The ICV infusion of gp120 for 3 days in rats could imitated the HAD animal model. Results of MWM test showed that the rats in the model group had longer escape latencies and errors compared with those in the control group (P < 0.01); Results of Western blot and PCR assay showed that the expressions of P2X7R and P2X7 mRNA in hippocampus of rats in the model group were significantly increased (P < 0.01). Conclusions The ICV infusion of gp120 in rats could imitate the HIV-1 associated dementia (HAD) animal models, and P2X7R may be involved in the pathophysiological process of learning and memory dysfunction caused by gp120.