Prior studies of mRNA expression, protein expression, and pathway metabolite levels have implicated dysregulation of the kynurenine pathway in the etiology of schizophrenia and bipolar disorder. Here we investigate whether genes involved in kynurenine pathway regulation might interact with genes that respond to kynurenine metabolites, to enhance risk for these psychiatric phenotypes. Candidate genes were selected from prior studies of genetic association, gene expression profiling and animal models. A single nucleotide polymorphism (SNP) in each of six genes, TDO2, HM74, HM74A, MCHR1, MCHR2 and MC5R, was tested for association with phenotype (475 Caucasians, 88 African Americans with schizophrenia; 97 Caucasians, 3 African Americans with bipolar disorder; 191 Caucasian, 49 African American controls). An A allele in HM74 was significantly associated with schizophrenia and with schizophrenia plus bipolar disorder combined, odds ratios (OR) of 1.48, p=0.011 and 1.50, p=0.007, respectively. Augmentation of disease risk was found for the complex genotype HM74[A,any]+MCHR1[T,any]+MCHR2[C,any] which conferred an OR maximal for the combined diagnostic category of schizophrenia plus bipolar disorder (1.70, p=0.003), carried by 30% of the cases. TDO2[CC]+MC5R[G, any]+MCHR2[GC] conferred an OR maximal for schizophrenia alone (4.84, p=0.005), carried by 8% of schizophrenia cases. The combined risk posed by these related, complex genotypes is greater than any identified single locus and may derive from co-regulation of the kynurenine pathway by interacting genes, a lack of adequate melanotropin-controlled sequestration of the kynurenine-derived pigments, or the production of melanotropin receptor ligands through kynurenine metabolism.