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Background: Previous studies have suggested an association between taking antidepressants and dental implant failure. This study aimed to investigate the association of different antidepressant classes with dental implant failure., Methods: This retrospective study included patients that received dental implants at the University of Florida from 2011 to 2016. The variables of implant failure, antidepressant use and classes (selective serotonin reuptake inhibitors [SSRI], serotonin-norepinephrine reuptake inhibitors [SNRI], tricyclic antidepressants [TCA], atypical antidepressants [AA], and monoamine oxidase inhibitors [MAOI]), age, sex, smoking, mild systemic diseases, and implant location were obtained from patients' records. Odds ratio (OR) and confidence interval (CI) of implant failure in patients taking different antidepressant classes, in relationship to non-antidepressant users, were estimated, and the influence of multiple variables on implant failure were investigated., Results: A total of 771 patients and 1,820 implants were evaluated. The statistically significant predictors for implant failure included smoking (OR = 5.221), use of antidepressants (OR = 4.285), posterior maxilla location (OR = 2.911), mild systemic disease (OR = 2.648), and age (OR = 1.037) (P <0.05). The frequency of implant failure was 33.3% in TCA users, 31.3% in SNRI users, 6.3% in SSRI users, 5.2% in Atypical antidepressant users, and 3.9% in non-users. Significant associations were observed between the use of SNRI (OR: 11.07; 95% CI: 3.265 to 33.82) and TCA (OR: 12.16; 95% CI: 1.503 to 71.58) and implant failure (P <0.05)., Conclusions: Users of antidepressants were at higher risk of implant failure than non-users. Patients taking SNRI and TCA were at the highest risk of implant loss, when compared with non-users. Conclusions about TCA, however, are based on a limited number of cases., (© 2020 American Academy of Periodontology.)