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Objective: Our objective was to improve understanding of the differences in cigarette use behavior and exposure for participants smoking their own brand of cigarettes in a clinical setting versus smoking under natural conditions. Methods: Adult daily smokers (N = 163) attended 2 clinic visits where they smoked through a CReSS™ topography device. Participants collected cigarette butts smoked without a CReSS™ device and completed a diary of location, mood, and activity for each cigarette smoked. Cigarette butts were used to determine mouth level nicotine (MLN). Least square means (LSMs) were estimated from mixed effects models. Results: The LSM for MLN was higher among participants who smoked cigarettes in the clinical setting. LSM MLN was 1.589 [95% CI: 1.312, 1.924] mg/cig for cigarettes smoked in the clinic and 1.087 [95% CI: 0.902, 1.310] mg/cig for cigarettes smoked outside of the clinic; we found differences between race and sex. Conclusions: Our results show nicotine intake and some smoking behavior are significantly biased upwards when studied in a clinical setting. Therefore, tobacco smoke exposure determinations in a clinical setting may not be completely generalizable to smoke exposure determinations in naturalistic settings. [ABSTRACT FROM AUTHOR]