Background. Solithromycin, a novel macrolide antibiotic with both intravenous and oral formulations dosed once daily, has completed 2 global phase 3 trials for treatment of community-acquired bacterial pneumonia. Methods. A total of 863 adults with community-acquired bacterial pneumonia (Pneumonia Outcomes Research Team PORT class II-IV) were randomized 1:1 to receive either intravenous-to-oral solithromycin or moxifloxacin for 7 once-daily doses. All patients received 400 mg intravenously on day 1 and were permitted to switch to oral dosing when clinically indicated. The primary objective was to demonstrate noninferiority (10% margin) of solithromycin to moxifloxacin in achievement of early clinical response (ECR) assessed 3 days after first dose in the intent-to-treat (ITT) population. Secondary endpoints included demonstrating noninferiority in ECR in the microbiological ITT population (micro-ITT) and determination of investigator-assessed success rates at the short-term follow-up (SFU) visit 5-10 days posttherapy. Results. In the ITT population, 79.3% of solithromycin patients and 79.7% of moxifloxacin patients achieved ECR (treatment difference, –0.46; 95% confidence interval CI, –6.1 to 5.2). In the micro-ITT population, 80.3% of solithromycin patients and 79.1% of moxifloxacin patients achieved ECR (treatment difference, 1.26; 95% CI, –8.1 to 10.6). In the ITT population, 84.6% of solithromycin patients and 88.6% of moxifloxacin patients achieved clinical success at SFU based on investigator assessment. Mostly mild/moderate infusion events led to higher incidence of adverse events overall in the solithromycin group. Other adverse events were comparable between treatment groups. Conclusions. Intravenous-to-oral solithromycin was noninferior to intravenous-to-oral moxifloxacin. Solithromycin has potential to provide an intravenous and oral option for monotherapy for community-acquired bacterial pneumonia. Clinical Trials Registration. NCT01968733.