OBJECTIVES: There is mixed evidence of association of serotoninergic genes with anorexia nervosa (AN), but substantial evidence for the involvement of serotonergic mechanisms in appetite control. This study was designed to investigate possible associations between the two subtypes of AN (Restricting-RAN, and Binge-purging-BPAN) and polymorphisms within five genes encoding for proteins involved in the serotoninergic system. METHODS: In order to carry out this investigation we have conducted a case-control association study on 226 females meeting the criteria for AN, and 678 matched healthy females. RESULTS: Our data show a significant association between polymorphisms with the gene encoding HTR2A with both AN subtypes, an association between polymorphisms within the genes encoding HTR1D and HTR1B with RAN, and an association between polymorphisms within the gene encoding HTR2C with BPAN. No associations were found for any polymorphisms of the serotonin transporter gene. This outcome indicates a substantial and complex inter-relationship between serotoninergic genes and AN. CONCLUSIONS: Given these data we hypothesis that the expression or control of expression of several genes of the serotoninergic system, and interactions between these genes, could exert considerable influence over the specific symptomatology of the subtypes of AN.