Objective To investigate the effect of antipsychotic quetiapine on the cell cycle of oligodendrocytes and its mechanism.Methods The oligodendrocyte precursor cells (OPCs) were treated with platelet-derived growth factor (PDGF, 10 ng/ml), quetiapine (10 μmol/L) or a mixture of the two for 48 h. Cell cycle, cell cycle exit index and cell differentiation were compared under different treatments. The relative mRNA expression levels of 8 cell cycle-related molecules in mice prefrontal cortex after intervention with quetiapine were measured. The effect of down-regulation of p21 by RNA interference on cell proliferation and differentiation was examined.Results PDGF induced a significant decrease in the percentage of cells in G0/ G1 phase (P < 0.05) and a significant increase in the percentage of cells in S phase and G2 phase (P < 0.05). Quetiapine inhibited the percentage increase of cells in S or G2 phase and prevented the percentage decrease of cells in G0/G1 phase induced by PDGF (P < 0.05). Treatment with PDGF inhibited cell cycle exit (P < 0.05), while quetiapine promoted cell cycle exit and blocked the influence of PDGF on cell cycle exit (P < 0.05). Quetiapine increased the maturation rate of OPCs and reduced the number of poorly-differentiated cells (P < 0.05). The expression of p21 was significantly increased after quetiapine intervention (P < 0.05). Down-regulation of p21 increased the percentage of S-phase cells (P < 0.05), decreased the percentage of G2-phase cells (P < 0.05), increased the number of bromodeoxyuridine-positive cells (P < 0.05), and decreased the number of myelin basic protein-positive cells (P < 0.05).Conclusions Quetiapine may involve in the differentiation of oligodendrocytes by regulating the cell cycle.