Polymorphisms within the 5-HT(2C) receptor gene promoter have been associated with several physiological and psychiatric phenotypes. Notably, the -759T allele has been associated with resistance to antipsychotic induced weight gain. This study assessed the activity of four promoter haplotypes expressed as luciferase constructs in the SH-SY5Y human neuroblastoma cell line in the presence or absence of a constitutively active 5-HT(2C) receptor. The presence of either -759T or -697C alleles reduced promoter activity. In addition a haplotype associated with resistance to antipsychotic induced weight showed under activity compared to the most common haplotype. In the presence of the 5-HT(2C) receptor a similar pattern of promoter activity was observed. Both -759C/T and -697G/C polymorphic sites are likely to play a role in basal promoter activity. Resistance to weight gain may, in part, be mediated by the consequences of reduced 5-HT(2C) receptor expression.