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Background: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous behavioral disorder, complex both in etiology and clinical expression. Both genetic and environmental factors have been implicated, and it has been suggested that gene-environment interactions may play a pivotal role in the disorder. Recently, a significant association was reported between ADHD and LPHN3 (which codes for latrophilin 3), and replicated in independent samples. Methods: We have examined the association between tag single nucleotide polymorphisms (SNPs) in LPHN3 within the region previously implicated in ADHD. Family based association tests (FBAT) were conducted ( n = 380 families) with the categorical diagnosis of ADHD, behavioral and cognitive phenotypes related to ADHD, and response to treatment (given a fixed dose of methylphenidate, 0.5 mg/day). Stratified FBAT analyses, based on maternal smoking and stress during pregnancy, was conducted. Results: Whereas limited association was observed in the total sample, highly significant interaction between four LPHN3 tag SNPs (rs6551665, rs1947274, rs6858066, rs2345039) and maternal stress during pregnancy was noted. Analysis conducted in the sub-group of mothers exposed to minimal stress during pregnancy showed significant associations with ADHD, behavioral and cognitive dimensions related to ADHD, as well as treatment response. Although extensive association was observed with the candidate SNPs, the findings are partially inconsistent with previously published results with the opposite alleles over-transmitted in these studies. Conclusions: These results provide evidence for the interaction between a genetic and environmental factor independently shown to be associated with ADHD. If confirmed in independent large studies, they may present a step forward in unraveling the complex etiology of ADHD. [ABSTRACT FROM AUTHOR]