<p>Congenital long QT syndrome (LQTS) conveys a significant risk of cardiac events. Primary management includes avoiding medications that prolong the QTc. Many antidepressant medications are known to be QT-prolonging, but there is scant literature on whether their use increases event rate or prolongs the QTc in LQTS. The objectives of this study are to determine the prevalence of depression and anxiety in patients with congenital LQTS, and to evaluate the effect of antidepressant treatment on frequency of LQTS-triggered events and QTc changes during antidepressant treatment. This was a single-center, retrospective study. Patients were divided based on whether they were prescribed antidepressants during the study period. Incidence of LQTS-triggered events and QTc measurements before and after antidepressant use were recorded for comparison. Ninety-eight subjects were identified for analysis. Most (92%) were prescribed beta-blockers as treatment for LQTS. 27% (<i>n</i> = 27) of the cohort were diagnosed with anxiety and/or depression. Of these, 15 received antidepressant therapy. We found no significant difference in the LQTS event rate or QTc measurements in patients prescribed antidepressants. Baseline median (IQR) QTc 467 (460, 479) ms vs. median (IQR) of first QTc post-antidepressant 482 (462, 487), <i>p</i> = 0.27. In this single-center study, the prevalence of anxiety and depression in patients with LQTS was consistent with the general population. Rates of treatment were also comparable. Our findings suggest that certain antidepressant therapy may be safe in patients with LQTS on beta-blockers. Further study across multiple centers and with a larger cohort may help clarify the safety of these medications.</p>