Rifampin is a potent hepatic cytochrome enzyme inducer, promoting the metabolism of many drugs. Here, we describe a case wherein rifampin-induced drug interactions affected the clinical improvement of a patient on psychiatric drugs for bipolar disorder. He was administered divalproex, risperidone, quetiapine, and clonazepam, along with anti-tuberculosis drugs HERZ, containing 600 mg rifampin. Despite taking 900 mg/day divalproex, his serum valproate levels were below 2 μg/ml, and his manic symptom persisted. Therefore, the antipsychotic risperidone (5 mg) was replaced with olanzapine (20 mg). Following this, his manic symptoms improved rapidly. Rifampin is a potent CYP3A and CYP2D6 inducer and is known to significantly reduce serum risperidone levels. Thus, even a high dose of risperidone did not induce a significant clinical effect, which was observed immediately after replacing with olanzapine. Therefore, drug interactions may have had a significant effect on clinical outcomes. Clinicians should be cognizant of drug interactions when treating psychiatric patients on rifampin therapy. The case has been sufficiently revised to protect the patient's personal information.