OBJECTIVES: Hyperplastic polyposis syndrome (HPS) confers an increased risk of colorectal cancer and is difficult to manage clinically. Because both polyps and resultant cancers display the CpG island methylator phenotype and mutation of the BRAF oncogene, and because sporadic cancers with these characteristics are associated with cigarette smoking, we hypothesized that cigarette smoking may predispose to the development of HPS. METHODS: This was a case–control study with two independent control series conducted at a tertiary hospital in Brisbane, Queensland, Australia. Cases comprised patients with HPS (n=32) recruited through the database of the Queensland Familial Bowel Registry, who satisfied the World Health Organization international classification for HPS. Cases were compared with colonoscopy controls (n=298) defined as consecutive patients undergoing colonoscopy for clinical indications, who were free from polyps. We also compared cases with a second set of population controls (n=645) selected at random from a population register serving the catchment area for cases. This was an observational study, and all participants completed a questionnaire to obtain a comprehensive smoking history. RESULTS: The prevalence rate of current smoking was 47% in HPS patients, 17% in colonoscopy controls, and 12% in population controls. HPS patients were significantly more likely to be current smokers than were either colonoscopy controls (odds ratio (OR)=8.3, 95% confidence interval (CI): 3.0–22.9) or population controls (OR=12.7, 95% CI: 4.9–33.1). CONCLUSIONS: Cigarette smoking is strongly associated with HPS, thus suggesting that smoking exposure may increase the expression of this condition. Further studies should examine the possible benefits of quitting smoking in HPS patients.