Background: To date, cigarette smoking is the most consistent risk factor for pancreatic cancer. We prospectively examined the role of active cigarette smoking, smoking cessation, and passive smoking as determinants for pancreatic cancer. Methods: The Netherlands Cohort Study consisted of 120,852 men and women who completed a baseline questionnaire in 1986. After 16.3 years of follow-up, 520 incident pancreatic cancer cases were available for analysis. A case-cohort approach was employed using the person-years of follow-up of a random subcohort (n = 5,000), which was chosen immediately after baseline. Results: Compared with never cigarette smokers, both former and current cigarette smokers had an increased pancreatic cancer risk [multivariable-adjusted hazard rate ratio (HR), 1.34; 95% confidence interval (CI), 1.02-1.75 and HR, 1.82; 95% CI, 1.40-2.38, respectively]. We observed an increased pancreatic cancer risk per increment of 10 years of smoking (HR, 1.15; 95% CI, 1.08-1.22) and an HR of 1.08 per increment of 10 cigarettes/d (95% CI, 0.98-1.19). Quitting smoking gradually reduced pancreatic cancer risk and approached unity after ≥20 years of quitting. No association was observed for passive smoking exposure and pancreatic cancer risk in women; in men, this association was not investigated because >90% of the men were ever smokers. Conclusions: Overall, our findings confirmed that cigarette smoking is an important risk factor for pancreatic cancer, whereas quitting smoking reduced risk. No association was observed between passive smoking exposure and pancreatic cancer risk in women. Impact: Quitting smoking would benefit the burden on pancreatic cancer incidence. ©2010 AACR.