Importance: Varenicline is the most effective sole pharmacotherapy for smoking cessation. If used in combination with nicotine replacement therapy (NRT), cessation rates may be further improved, but the efficacy and safety of the combination need to be evaluated.

Question: Does the combination of varenicline and nicotine lozenges improve smoking cessation rates in hospitalized smokers compared with varenicline alone?

Findings: In this randomized clinical trial of 320 adult daily smokers, the combination of varenicline and nicotine lozenges initiated during hospitalization did not improve biochemically verified abstinence, the primary outcome, which was affected by COVID-19 restrictions; however, self-reported smoking abstinence at 6 and 12 months, the main secondary outcomes, were higher in the combination group than the varenicline-alone group.

Meaning: Smokers wishing to quit have an additional pharmacologic treatment option in the form of varenicline and nicotine lozenges that may be safely used in combination, but additional studies may be needed to confirm its effectiveness.