Background: We sought to investigate and compare the safety and efficacy of two commonly used antiarrhythmic drugs, Dofetilide (DF) and Sotalol (SL), during inpatient drug initiation in patients with symptomatic atrial fibrillation (AF). Methods: We performed a single center retrospective study of consecutive patients, admitted for initiation of either DF or SL, for AF between 2012 and 2015. Rates of successful cardioversion, QT interval prolongation, adverse events and drug discontinuations were calculated and compared. A two-tailed p value less than 0.05 was considered statistically significant. Results: Of 378 patients, 298 (78.8%) received DF and 80 (21.2%) SL, mean age was 64 ± 11 years, 90% were Caucasians and 66% were males. Among the patients who remained in AF upon admission (DF: 215/298 (72%) vs. SL: 48/80 (60%)), no significant differences were noted in pharmacological cardioversion rates (DF: 125/215(58%) vs. SL: 30/48 (62.5%); p = 0.58). Baseline QTc was similar between the groups, with higher dose dependent QTc prolongation with DF (472.25± 31.3 vs. 458± 27.03; p = 0.008). There were no significant differences in the rates of adverse events such as bradycardia (7.4% vs. 11.3%; p = 0.26), Torsades de pointes (1.3% vs. 1.2%; p = 1.00), and drug discontinuation (9.0% vs. 5.0%; p = 0.47) between the two groups. Conclusion: In our large, single center experience, we found that the use of Dofetilide resulted in significantly higher QTc without differences in the rates of successful cardioversion, adverse events, and drug intolerance when compared to Sotalol in AF patients.