OBJECTIVE To study the effects of clozapine and risperidone on serum cytokine levels in patients with first-episode paranoid schizophrenia, and explore the role of the cytokines in the psychopathological basis of the illness. METHODS Fifty-eight patients with first-episode paranoid schizophrenia were treated with either clozapine or risperidone, and before and at the end of the 4th, 8th weeks and 6th months after the medication respectively, the serum levels of interleukin (IL)-6, 2, 18,and tumor necrosis factor (TNF)alpha were measured with enzyme-linked immunosorbent assay (ELISA). The Positive and Negative Syndrome Scale (PANSS) was used to evaluate the psychotic symptoms. RESULTS In patients treated with risperidone, the levels of serum IL-6 and IL-2 after 4 weeks, TNFalpha after 8 weeks, and IL-18 after 6 months were all significantly lowered in comparison with the pretreatment levels (P<0.01 or 0.05). In clozapine group, the levels of IL-2 after 4 weeks and IL-6 and IL-18 after 6 months were lowered significantly (P<0.01 or 0.05). Before the medication, serum IL-6 level was positively correlated with Positive Syndrome scores (r=0.386, P<0.01), IL-2 with the total score and Positive Syndrome scores (r=0.338, 0.305; P<0.01, 0.05), and TNFalpha with the total score (r=0.283, P<0.05). The changes of IL-2 and IL-6 after 8 weeks was positively correlated with the change of Positive Syndrome scores (r=0.268, 0.375; P<0.05, 0.01). Six months after the medication, the change in IL-6 and TNFalpha levels was positively correlated with the change of total score (r=0.365, 0.362; P<0.05). Before treatment, IL-6 was positively correlated with IL-2 levels (r=0.356, P<0.01), and TNFalpha with IL-18 levels (r=0.291, P<0.05). TNFalpha was positively correlated with IL-6 levels (r=0.332, P<0.01) 8 weeks after the medication. The changes in IL-6 was positively correlated with the those in IL-2 levels 6 months after the medication (r=0.391, P< 0.05). CONCLUSIONS Clozapine and risperidone have similar immunosuppression actions and may affect serum IL-6 levels in patients with paranoid schizophrenia, in the psychopathology of which the cytokines play their roles of various importance.