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Abstract: Background: Complex behaviors such as suicidal behavior likely exhibit gene–gene interactions. The main aim of this study is to explore potential single nucleotide polymorphisms combinations with epistatic effect in suicidal behavior using a data mining tool (Multifactor Dimensionality Reduction). Methods: Genomic DNA from peripheral blood samples was analyzed using SNPlex Technology. Multifactor Dimensionality Reduction was used to detect epistatic interactions between single nucleotide polymorphisms from the main central nervous system (CNS) neurotransmitters (dopamine: 9; noradrenaline: 19; serotonin: 23; inhibitory neurotransmitters: 60) in 889 individuals (417 men and 472 women) aged 18years or older (585 psychiatric controls without a history of suicide attempts, and 304 patients with a history of suicide attempts). Individual analysis of association between single nucleotide polymorphisms and suicide attempts was estimated using logistic regression models. Results: Multifactor Dimensionality Reduction showed significant epistatic interactions involving four single nucleotide polymorphisms in female suicide attempters with a classification test accuracy of 60.7% (59.1%–62.4%, 95% CI): rs1522296, phenylalanine hydroxylase gene (PAH); rs7655090, dopamine receptor D5 gene (DRD5); rs11888528, chromosome 2 open reading frame 76, close to diazepam binding inhibitor gene (DBI); and rs2376481, GABA-A receptor subunit γ3 gene (GABRG3). The multivariate logistic regression model confirmed the relevance of the epistatic interaction [OR(95% CI)=7.74(4.60–13.37)] in females. Conclusions: Our results suggest an epistatic interaction between genes of all monoamines and GABA in female suicide attempters. [Copyright &y& Elsevier]