Background and Objectives <p>Viloxazine (extended-release [ER] capsules) is a nonstimulant medication approved for the treatment of pediatric (aged ≥ 6 years) and adult attention deficit hyperactivity disorder. This study assessed the effect of hepatic impairment (HI) on the pharmacokinetics, safety, and tolerability of viloxazine ER.</p> Methods <p>In this open-label, multicenter study, adults (18–78 years) with mild (<i>n</i> = 8), moderate (<i>n</i> = 8), or severe (<i>n</i> = 8) HI (Child–Pugh classification) and a demographically matched control cohort with normal hepatic function received a single oral dose of viloxazine ER (200 or 400 mg), following a ≥ 10-h overnight fast. Blood samples were collected for 72 h post-administration and analyzed for viloxazine and its primary metabolite 5-hydroxy-viloxazine glucuronide. The potential for HI to impact pharmacokinetics was evaluated using relative bioavailability analysis of viloxazine maximum measured plasma concentration (<i>C</i>_max) and area under the concentration–time curve (AUC) parameters and comparison of time to <i>C</i>_max (<i>T</i>_max) and terminal elimination half-life (<i>t</i>_1/2). Safety and tolerability were also evaluated<b>.</b></p> Results <p>In adults with versus without HI (any severity), there were no significant differences in viloxazine <i>C</i>_max (mean ± standard deviation [SD] for mild HI, 3.1 ± 1.0 µg/mL versus 2.4 ± 0.4 µg/mL; moderate HI, 2.5 ± 0.8 µg/mL versus 2.5 ± 0.6 µg/mL; severe HI, 1.3 ± 0.4 µg/mL versus 1.5 ± 0.2 µg/mL) and AUC (from time 0 to infinity; mean ± SD for mild HI, 70.5 ± 19.3 h·µg/mL versus 56.8 ± 8.6 h·µg/mL; moderate HI, 62.8 ± 28.9 h·µg/mL versus 60.4 ± 20.5 h·µg/mL; severe HI, 42.0 ± 16.4 h·µg/mL versus 33.1 ± 9.7 h·µg/mL), and mean exposure for those with HI was within 25% of matched control values. Increased <i>t</i>_1/2 was observed in moderate and severe HI versus controls (mean ± SD for mild HI, 7.6 ± 3.1 h versus 6.7 ± 2.5 h; moderate HI, 9.3 ± 3.1 h versus 6.0 ± 1.7 h; severe HI, 14.2 ± 5.8 h versus 7.1 ± 2.7 h). No adverse event (AE) was reported by ≥ 2 study participants with HI. The most common AEs were headache (<i>n</i> = 1 mild HI, <i>n</i> = 2 healthy controls) and somnolence (<i>n</i> = 2 healthy controls).</p> Conclusions <p>Mild-to-severe HI showed minimal impact on viloxazine ER exposure. The single dose of viloxazine ER was well-tolerated with no identified safety concerns.</p>