Clozapine is the drug of choice for treatment-resistant schizophrenia. However, its use is associated with variable clinical responses and serious adverse effects. Polymorphisms in genes encoding proteins involved in synaptic neurotransmission may account for such variability. Here, we studied independent and epistatic genetic associations of polymorphisms in DRD4 (120-bp duplication) and COMT (Val158Met) with clinical response to clozapine in people with treatment-resistant schizophrenia. We studied 93 participants who were on stable doses of clozapine for at least 12 weeks. A total score of less than or equal to 35 on the Brief Psychiatric Rating Scale was defined as a clinical response. The genetic associations were tested using logistic regression analyses. Neither polymorphism studied was found to be independently associated with response to clozapine. However, a statistically significant gene–gene interaction was observed between the polymorphisms. Participants with the COMT Val/Met or Met/Met genotype, who also had one or two DRD4 120-bp alleles (120/240 and 120/120), showed significantly better clinical response to clozapine. Our results highlight the importance of investigating gene–gene interactions, while studying the pharmacogenetics of clozapine.