Objectives. Increasing drug expenditures call for better understanding of the reasons behind individual general practitioners' (GPs') prescribing decisions. The aim was to analyse associations between GPs' clinical interests and their preference for new drugs. Design. Historical cohort study using population-based prescription data and data collected by postal questionnaire. Setting and subjects. A total of 68 single-handed GPs in the County of Funen, Denmark. Main outcome measures. GPs' preferences for two new (2004) drug groups (selective cyclo-oxygenase-2 inhibitors and angiotensin-II antagonists) were analysed. The preference was defined as the percentage of patients receiving a new drug among first-time users of either the new drug or an older alternative. The GPs' preference proportion was modelled using linear regression analysis. Data from a questionnaire on GPs' interest in corresponding clinical areas (musculoskeletal diseases and hypertension, respectively), continuing medical education (CME) activities, and previous employment were the independent variables. Results. The adjusted mean difference in preference for new drugs between GPs with high and low interest in each of the two clinical areas was 0.4% (95% CI-2.0% to 2.8%), and-2.2% (-15.0% to 10.7%), respectively. Only current CME activities in the area of hypertension were significantly associated with GPs' preference for new drugs (adjusted mean difference 17.9% (95% CI 5.8% to 30.0%). Conclusion. No clear association between GPs' self-rated clinical interest and their prescribing of new drugs was found.