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Recent evidence from randomized clinical trials (RCTs) of very low nicotine content (VLNC) cigarettes indicates that smokers randomized to VLNC cigarettes had significantly lower cigarette use, dependence, and biomarkers of exposure than smokers randomized to normal nicotine content control cigarettes. In these trials, a substantial number of participants did not adhere to their randomized treatment assignment, i.e., they used commercial cigarettes not provided by the trial in place of or in addition to the VLNC cigarettes provided by the trial. As with most RCTs, the analysis of these trials followed the intention-to-treat principle, where participants are analyzed according to their randomized treatment assignment regardless of adherence. Alternately, the analysis of an RCT could focus on the estimation and testing of the causal effect of the intervention, which is the treatment effect if all subjects were to adhere to their randomized treatment assignment. In this commentary, we compare these two approaches, highlighting the important role of causal estimation and inference for evaluating the regulatory effect of a nicotine standard for cigarettes. Additionally, we review the results of the secondary analyses of randomized trials of VLNC cigarettes using causal inference methodology to account for non-adherence to the assigned treatment and discuss the implications for a nicotine standard for cigarettes. [ABSTRACT FROM AUTHOR]