Introduction: Recent genetic evidence has implicated nicotine as a possible cause of cancer, suggesting the need to examine the potential contributions of nicotine itself to cancer versus the confounding effects of addiction and thus exposures to known carcinogens. The objective of this study was to examine the relationship between nicotine replacement therapy, smoking, and cancer outcomes. Methods: The Lung Health Study enrolled 5,887 participants in a randomized trial to prevent chronic obstructive pulmonary disease. The present study used surveillance data on 3,320 intervention participants who enrolled in the Lung Health Study for 5 years and who were then followed by the Lung Cancer Substudy for 7.5 years. Nicotine replacement therapy use and smoking exposure were recorded during the 5-year Lung Health Study trial. Surveillance for lung cancer, gastrointestinal cancer (including oral cancers), and all cancers began following the Lung Health Study. Results: Adjusted Cox proportional hazards regressions assessed the hazards of nicotine replacement therapy and smoking for each diagnosis group. In the adjusted models for lung cancer, nicotine replacement therapy alone was not a significant predictor (p = .57), while smoking during the Lung Health Study was a significant predictor (p = .03). When nicotine replacement therapy and smoking were entered in the same model, nicotine replacement therapy remained not significant (p = .25) and smoking was clearly significant (p = .02). Nicotine replacement therapy and smoking were not significant predictors of cancer in the models for gastrointestinal cancer or all cancers. Discussion: Although the surveillance time was short, smoking predicted cancer in this analysis and nicotine replacement therapy did not.