Clozapine is an atypical antipsychotic agent with immunomodulatory properties. We hypothesized that in vitro immune parameters of peripheral blood mononuclear cells (PBMC) are affected in the course of clozapine treatment and that clozapine per se, added in vitro to PBMC cultures of clozapine-treated patients, exerts differential effects in the timecourse of treatment in vivo. We measured proliferation and cytokine secretion of PBMC, serum autoantibodies, and immunoglobulin levels in 17 patients before and during the first 6 weeks of clozapine treatment. Independent of clozapine dosage and rectal temperature, clozapine treatment in vivo suppressed proliferation and shedding of sIL-2r by PBMC, and the addition of clozapine in vitro induced, relative to unstimulated conditions, PBMC proliferation and secretion of IL-6 and sIL-2r. Serum IgG levels were increased; whereas, autoantibody pattern was unaffected. Thus, clozapine treatment and the addition of clozapine in vitro exert differential effects on various in vitro immune parameters independent of clozapine dosage and rectal temperature in the course of treatment.