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Background: Tobacco use is the leading preventable cause of cancer and premature death, smoking has a clear causal relationship with a variety of cancers. However, the relationship between exposure to secondhand smoke (SHS) and other cancers besides lung cancer is not clear. In this study, we intend to investigate the cancers mortality risks especially other cancers besides lung cancer associated with exposure to SHS. Methods: The National Health and Nutrition Examination Survey is a longitudinal population-based, nationally representative health survey and mortality rates linked to the National Death Index (NDI) database. In this study, the participants completed a questionnaire assessing sociodemographic data, anthropometry, and lifestyle information, including smoking and alcohol consumption, meanwhile, all the participants were screened for serum cotinine. First, Spearman correlation analysis was performed to confirm the correlation between serum cotinine level and exposure status. And then, exposure to SHS was divided into two groups: low exposure group (serum cotinine level between 0.015 and 10) and high exposure group (serum cotinine level ≥ 10), Cox proportional hazards regression modeling was used to evaluate the association between exposure to SHS and eight different types of smoke-related cancer. Results: In this study, we evaluated a cohort of 25,794 US residents older than 19 years from 2005 to 2016 and were followed for mortality through the February 2019. We conducted Spearman correlation analysis to confirm the correlation between serum cotinine level and exposure status (including smoking and exposure to SHS), it demonstrated the correlation coefficient between serum cotinine level and exposure to smoke was 0.976, p < 0.00001. By Cox proportional hazards regression modeling, high exposure group were found to be positively associated with all neoplasms with a total Hazard Ratio (HR) of 1.748 (95% Confidence Interval (CI), 1.415–2.159), had higher all-cause mortality risks than non-exposure to tobacco smoke. Regarding the specific types, we found the following associations: cancer of the lung (HR, 1.484; 95% CI, 1.191–1.849), stomach (HR, 1.491; 95% CI, 1.199–1.854), bladder (HR, 1.487; 95% CI, 1.198,1.846), esophageal (HR, 1.487; 95% CI 1.194–1.852), kidney (HR, 1.497; 95% CI, 1.201–1.865), pancreatic (HR, 1.479; 95% CI 1.189–1.841), leukemia (HR, 1.479; 95% CI 1.190–1.839), cervical (HR, 1.490; 95% CI 1.198–1.853). However, low exposure group were non-existent statistically significant with a Hazard Ratio (HR) of 1.062 (95% Confidence Interval (CI), 0.953–1.183). Conclusions: The research demonstrated that serum cotinine has a significant correlation with smoke exposure status, which confirmed serum cotinine can be used as an indicator to reflect human smoke exposure. What's more, our results confirmed high exposure of SHS (serum cotinine level ≥ 10) has a significant effect on lung, stomach, bladder, esophagus, kidney, pancreatic, leukemia, cervical cancer. [ABSTRACT FROM AUTHOR]