Background: The impact that smoking cigarettes has on the characteristics and survival of patients with non-small cell lung cancer (NSCLC) is disputed. Methods: A retrospective cohort study using a prospective database of patients with NSCLC over a 6-year period. Clinical and histologic characteristics and survival rates were compared between smokers and never-smokers. Results: There were 730 patients; 562 patients (77%) were smokers and 168 patients (23%) were never-smokers. The overall 5-year survival rate was greater in never-smokers (64%) compared to smokers (56%; p = 0.031). Never-smokers were more likely to be younger (p = 0.04), female (p = 0.01), symptomatic at the time of presentation (p < 0.001), have poorly differentiated tumors (p = 0.04), and have a higher maximum standardized uptake value (maxSUV) on positron emission tomography (PET) (p = 0.026) than smokers. The stage-specific 5-year survival rate was greater for never-smokers compared to smokers for stage I disease (62% vs 75%, respectively; p = 0.02), stage II disease (46% vs 53%, respectively; p = 0.09), and stage III disease (36% vs 41%, respectively; p = 0.13). The 5-year survival rate was significantly lower in patients who had a smoking history of > 20 pack-years. Conclusions: Never-smokers in whom NSCLC develops are more likely to be young, female, and have poorly differentiated tumors with higher maxSUV values on PET scans. Never-smokers with early-stage cancer have a significantly better survival rate than smokers. Patients with a smoking history of ≥ 20 pack-years have worse survival. Thus, smoking not only causes lung cancer, but once NSCLC is diagnosed, the prognosis becomes worse. A biological, hormonal, and genetic explanation is currently lacking to explain these findings, and these data may help to improve treatment and surveillance.