The aim of this study was to evaluate prospectively smoking dependence as a predictor of repeated use of prescribed opioids in non-cancer patients.We conducted a prospective population-based study cohort of 12,848 men and 15,894 women 30–75 years of age in health surveys in Norway during 2000–2002 with repeated opioid prescriptions (12+, during 2004–2007) recorded in the Norwegian Prescription Database as the outcome measure. Information on history of smoking and potential confounders was obtained at baseline by self-administered questionnaires. For smoking, participants were divided into categories: never; previously heavy (stopped maximum of 5 years earlier; 10+ cigarettes daily); daily not heavy (1–9 cigarettes); dependent daily smokers (10+ cigarettes), and other (previously and/or not daily). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by logistic regression.During follow-up, 335 (1.5%) of survey participants were registered with 12+ prescriptions of opioids during the period 2004–2007. The prevalence of repeated prescription frequency of opioids was higher for men and women with a history of smoking. The adjusted OR for prescribed opioids for dependent daily smokers was 3.1 (95% CI: 2.3–4.1), for daily non-heavy smokers 1.8 (1.2–2.7), and for previous heavy smokers 1.8 (1.1–3.0), compared with never-smokers as reference.Results of the study suggest that smoking dependence may predict more frequent use of opioids.