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LY03004, a novel investigational risperidone long-acting injection (LAI) microsphere formulation, can release risperidone more quickly after injection than Risperdal Consta®. This study aimed to investigate the effects of genetic polymorphisms on the pharmacokinetics of LY03004 compared with those on Risperdal Consta®. A total of 100 Chinese patients with stable schizophrenia were randomly assigned to the LY03004 or Risperdal Consta® treatment group. Each patient received five biweekly intramuscular injections of 25 mg risperidone long-acting injection microspheres. A total of 34 blood samples before and after injections from Day 1 to Day 113 were collected from each patient, and polymorphic alleles of cytochrome P450 enzymes CYP2D6 (*4, *10, *14), CYP3A5 (*3), and ABCB1 (C1236 > T, G2677T/A , and C3435T) were analyzed using Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism. The risperidone C max,ss , C min,ss , AUC 0-tau,ss , and the ratio of risperidone to 9-hydroxyrisperidone (9-OH-R) in CYP2D6 intermediate metabolizers (IMs) were significantly different compared with those in normal metabolizers (NMs) in both the LY03004 and Risperdal Consta® groups (P < 0.05). However, 9-OH-R was not significantly different between IMs and NMs (P > 0.05). The AUC 0-tau,ss of the active moiety (risperidone plus 9-OH-R) was 6.51 ± 3.34 in NMs and 7.00 ± 1.81 in IMs (P = 0.071) in the LY03004 group and 6.07 ± 2.31 and 7.95 ± 3.42 (P = 0.053) in NMs and IMs, respectively, in the Risperdal Consta® group. In the LY03004 group, the C max,ss of risperidone in carriers of the ABCB1-C3435T TT variant was significantly lower than that in CC and CT carriers (TT 7.76 ± 4.23 ng/mL, CT 11.6 ± 8.27 ng/mL, CC 14.3 ± 7.66 ng/ml; P = 0.045), but no significant differences were found in the active moiety. In the Risperdal Consta® group, C3435T TT carriers had significantly lower C min,ss of the active moiety (TT 5.09 ± 4.38 ng/mL, CT 11.4 ± 8.42 ng/mL, CC 14.3 ± 6.43 ng/mL; P = 0.007). Furthermore, C min,ss of the active moiety was significantly different among all ABCB1-G2677T/A genotypes (P < 0.05). The pharmacokinetics of risperidone and the ratio of risperidone to 9-OH-R were highly dependent on CYP2D6 activity. However, there was no significant effect in 9-OH-R. A future study involving a larger sample is required to verify whether CYP2D6 IMs have lower risperidone active moiety clearance than CYP2D6 NMs for LAI formulations. In addition, the risperidone active moiety was eliminated faster in ABCB1-G2677T/A and C3435T TT carriers receiving Risperdal Consta®. • We analyzed the effects of CYP2D6, 3A5, and ABCB1 gene polymorphisms on the pharmacokinetics of risperidone LAIs in Chinese. • IMs had significantly higher exposure to risperidone than CYP2D6 NMs; however, no significant difference in 9-OHRIS. • IMs probably had higher active moiety exposure than NMs, but a study with a larger sample is required to verify the results. • G2677TA and C3435T TT carriers receiving Risperdal Consta® injection had significantly lower C min,ss of the active moiety. • Formulation may be an influence factor that affects the level of risperidone exposure differences among different genotypes. [ABSTRACT FROM AUTHOR]