To compare use of electronic nicotine delivery systems (ENDS) with nicotine replacement therapies (NRTs) on risk of cigarette smoking relapse by people who had already quit cigarettes.

Prospective cohort study.

The American Cancer Society Cancer Prevention Study-3, a nationwide US cohort with follow-up every 3 years beginning in 2015.

Adults who in 2015 had already quit smoking (n=3112) or were smoking (n=1018) and who in 2018 reported past or current exclusive use of ENDS or NRT and provided smoking status.

Relapse to cigarette smoking in 2018 among people who were already quit in 2015, and abstinence from cigarettes in 2018 among people who were smoking in 2015.

Among respondents who had already quit in 2015, the unadjusted risk of relapse in 2018 was approximately three times greater for those who reported past exclusive ENDS versus past exclusive NRT use (11.2% vs 3.9%; relative risk (RR)=2.90, 95% CI 2.12 to 3.98). This association remained significant in a multivariable-adjusted model (RR=2.09, 95% CI 1.49 to 2.92). Among those smoking in 2015, the unadjusted likelihood of abstinence in 2018 was higher for those who reported current ENDS versus NRT use (RR=1.35, 95% CI 1.01 to 1.80), but the multivariable model adjusted for smoking frequency indicated no difference in abstinence (RR=1.38; 95% CI 0.93 to 2.05).

ENDS use was associated with greater relapse risk than NRT among people who had already quit. Although ENDS may support shorter-term cessation, further long-term observational research is needed to clarify relapse risks associated with ENDS relative to NRT.