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Abstract Objective The serotonin-transporter-linked polymorphic region (5-HTTLPR) polymorphisms are associated with suicidal behavior; however, prospective studies are scarce. Herein we aim to determine if 5-HTTLPR polymorphisms predict risk of short-term suicide reattempt in a high-risk suicidal sample. We also explore possible mediators or moderators of this relationship. Methods A multicenter prospective cohort study was designed to compare data obtained form 136 patients admitted to the emergency department for current suicidal ideation or a recent suicide attempt. Subjects were clinically evaluated, genotyped, and monitored for a new suicide attempt for 6 months. Results At 6 months of follow up, 21% of the subjects had a new suicide attempt. The frequency of L-allele and L-carrier was higher in reattempters when compared with non-reattempters (55.8% vs. 35.4%, p = 0.01 and 76.9% vs. 54.2%, p = 0.04, respectively). Reattempters also differ from non-reattempters patients with respect to age, history of previous suicide attempts, and age of onset of suicidal behavior. The logistic regression model showed that L-carriers had an odds ratio of 2.8 (95% CI: 1.0–7.6) for reattempts when compared to SS genotype. The adjusted model indicates that this association is not mediated or moderated by impulsivity. Conclusion The 5-HTTLPR polymorphisms predicted short-term risk of suicidal reattempt independently of age and sex. L-carriers have almost three times more risk of relapse when compared with SS carriers. [ABSTRACT FROM AUTHOR]