Suicidal behavior and substance abuse are frequent phenomena among patients with schizophrenia and may be attributable in part to antipsychotic treatment failure. Individuals who carry functional variants of the CYP2D6 and CYP2C19 genes, shown to cause altered drug metabolism of psychoactive drugs, are at risk of toxic accumulation or rapid elimination of these drugs, leading to treatment failure. We tested whether substance abuse disorder and suicidal behavior were associated with the CYP2D6 and CYP2C19 genotypes among patients with schizophrenia. Three hundred sixty-two patients with schizophrenia spectrum disorders (International Classification of Diseases, 10th Revision) were genotyped for functional CYP2D6 and CYP2C19 polymorphisms. Based on available medical records and clinical interviews, their suicidal behavior and substance abuse disorder were evaluated. No significant associations between the CYP2D6 and CYP2C19 genotypes and suicidal behavior or substance abuse disorder were noted, and we conclude that cytochrome P450 genotyping in its present form is clinically irrelevant with respect to these phenomena.