OBJECTIVE: Association has been reported between the C allele of a –759C/T polymorphism in the promoter of the 5-HT2C receptor gene (HTR2C) and antipsychotic-induced weight gain, suggesting that polymorphic HTR2C expression influences this phenotype. The authors tested this polymorphism, and other promoter variants, for effects on HTR2C transcription. METHOD: Six HTR2C promoter haplotypes constructed from four polymorphisms were cloned into a luciferase reporter gene plasmid. Their transcriptional activities were then compared in two human cell lines. RESULTS: All haplotypes containing the –759C allele showed less transcriptional activity than haplotypes containing the –759T allele. The A allele of a –997G/A polymorphism was also associated with reduced expression. CONCLUSIONS: These findings suggest that the –759C allele is functional and results in relative underexpression of HTR2C. Reduced expression of HTR2C mRNA may underlie vulnerability to weight gain following antipsychotic treatment.