Objective: Positive associations between polymorphisms in the type-three metabotropic glutamate receptor gene (GRM3) and the pathogenesis of schizophrenia as well as response to antipsychotic treatment have been reported. The objective of this study was to determine whether refractory psychiatric symptoms in antipsychotic non-responders are related to polymorphisms in GRM3. Methods: Ninety-five treatment refractory schizophrenia participants were enrolled. Prior to a medication switch, global psychopathology and negative symptoms were rated. These participants were genotyped for seven markers in GRM3. Genotype associations with symptoms were assessed. Results: Two markers in GRM3 (rs1989796 and rs1476455), were associated with the presence of refractory global symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) Total scores. Participants with an rs1476455-CC genotype had significantly higher BPRS scores than A-carriers (55.1±10.4 vs. 48.3±9.2; F=7.6, p=0.0071). Additionally, participants with the rs1989796-CC genotype had significantly higher BPRS scores than T-carriers (50.1±5.7 vs. 55.8±10.5, F=7.1, p=0.0091). No evidence for significant associations with negative symptoms was observed. Conclusions: Polymorphisms in the GRM3 gene may be associated with refractory global psychosis symptoms but not negative symptoms in persons with schizophrenia.