Weight gain and metabolic syndrome are the most common deleterious side effects following treatment with second generation antipsychotic drugs such as clozapine and olanzapine. However, the mechanisms underlying these negative effects of second generation antipsychotic drugs are not fully understood. In this study we investigate whether variants in the genes coding for the α-catalytic (PRKAA1, PRAKAA2) and the β regulatory subunits (PRKAB1 and PRKAB2) of the cellular energy sensor AMP-activated protein kinase (AMPK) are associated with antipsychotic-induced weight gain. To accomplish this, ten polymorphisms in 208 schizophrenia or schizoaffective disorder patients treated with clozapine, haloperidol, risperidone or olanzapine for up to 14 weeks were analyzed. Significant association was observed between rs3766522 in PRKAB2 (AA vs. AT + TT; p = 0.022) and rs10789038 in PRKAA2 (GG + GA vs. AA, p = 0.023) with weight change (%) in patients of European ancestry following treatment with clozapine or olanzapine. Allelic association of the T-allele of rs3766522 (p = 0.019) and the G-allele of rs10789038 (p = 0.041) with weight change (%) was also observed. Analysis of raw weight gain revealed that carriers of the T-allele of rs3766522 (AT + TT, 4.3 kg ± 3.7) gained more weight than the AA-genotype carriers (2.5 kg ± 4.5, p = 0.042). Similarly, carriers of the G-allele of rs10789038 (GG + GA, 4.2 kg ± 4.5) gained more weight than AA-homozygotes (1.5 kg ± 2.9, p = 0.014) under antipsychotic treatment. In conclusion, we observed significant associations between polymorphisms in AMPK subunit genes and weight gain induced by clozapine and olanzapine.