The cytochrome P450 2D6 (CYP2D6) metabolizes around 20% of currently prescribed medications, including the antipsychotic risperidone. Previous studies reported greater odds of switching antipsychotic medication from risperidone among CYP2D6 poor metabolizers (PM) without considering treatment duration up to the switch. Risperidone treatment failure, defined as risperidone treatment duration up to switching medication, was analyzed among 515 patients of the PsyMetab cohort using Kaplan-Meier estimates with log-rank tests and Cox multivariate regression. Risperidone-to-paliperidone ratios were higher among CYP2D6 PMs (median: 2.78) vs. the other phenotypes (median: 0.14, P < 0.001). After 1 year of treatment, the proportion of patients who switched from risperidone was 44%. This proportion was increased to 70% among PMs, vs. 42% among the other CYP2D6 phenotypes (P = 0.026). PMs' risk of switching increased over time (interaction PM*treatment duration: 1.01; P = 0.011), becoming statistically significant after 3 months of treatment, with 1.79 (P = 0.028), 3.7 times (P < 0.001) and 16.3 times higher (P = 0.001) risk of switch at 3, 6, and 12 months, respectively (95% confidence intervals: 1.07-3.01, 1.91-7.17, and 3.13-85.37, respectively). Considering a pharmacogenetic-guided treatment, the number of patients needed to genotype to find one PM and lower the switching proportion from 70% to 42% would be 65. In conclusion, CYP2D6 PM status presented an increased risk of switching from risperidone over 1 year of treatment, the risk increasing over time and becoming statistically significant after the first 3 months of treatment.