Objective: A single-institution case–control study was conducted to test the hypothesis that a history of smoking was associated with a higher risk of developing MPNs compared to CLL. Methods: Cases (n = 323) were all MPN patients diagnosed in a 10-year period, and controls (n = 333) were all patients with CLL diagnosed during that same period. Odds ratios and 95% confidence intervals were calculated and adjusted for gender and age by logistic regression. Results: A significant association between a personal history of smoking and the risk of MPNs compared to CLL were observed for all MPNs (OR = 1.73, 95%CI 1.25–2.40) and for the WHO 2008 classified MPNs (OR = 1.64, 95%CI 1.16–2.30). Conclusions: No other larger case–control study has described a positive association between the risk of MPN and a history of smoking in the general MPN population. This association might be explained by the chronic inflammatory state and oxidative stress in response to smoking, eliciting genomic instability in the stem cell compartment and ultimately clonal evolution resulting in MPNs.