Objectives: A positive correlation between antipsychotic-induced weight gain (AIWG) and the antagonist effect of antipsychotic drugs at the histamine H1 receptor (HRH1) as well as the agonist effect at the histamine H3 receptor (HRH3) in the brain has been consistently demonstrated. We investigated the potential impact of single-nucleotide polymorphisms (SNPs) in HRH1 and HRH3 genes on AIWG. Methods: We analysed 40 tagSNPs in HRH1 ( n = 34) and HRH3 ( n = 6) in schizophrenia/schizoaffective disorder patients ( n = 193) primarily treated with clozapine or olanzapine for up to 14 weeks. Linear regression was used to evaluate the association between SNPs and AIWG, with baseline weight and treatment duration as covariates. Results: In HRH1, a nominal association of rs7639145 with AIWG was observed in patients of European ancestry treated with either clozapine or olanzapine ( P = 0.043; β = 1.658; n = 77). We observed nominal association for two HRH1 SNPs rs346074 ( P = 0.002; β = –5.024) and rs13064530 ( P = 0.004; β = –5.158) in patients of African ancestry treated with either clozapine or olanzapine ( n = 37). However, the above associations are not significant after correcting for multiple testing. In HRH3, we did not observe association in either ancestry. Conclusions: The current study suggests that SNPs in HRH1 and HRH3 may not have a major role in AIWG.