OBJECTIVES: The study investigated (1) the association between comorbidity and multidrug prescribing compared with the index condition, and (2) the association between vascular comorbidity and non-vascular condition key drug prescribing. DESIGN: Cross-sectional study linking anonymised computer consultations with prescription records for a 2-year time period. SETTING: 11 general practices in North Staffordshire, England. PARTICIPANTS: Study groups aged 40 years and over (N=12 875). Within six conditions, comorbid group with the other five conditions was compared with an 'alone' group without them. Additionally, how the 'vascular' (one of diabetes, cardiovascular disease and cerebrovascular disease) comorbidity influenced chronic obstructive pulmonary disease (COPD), osteoarthritis (OA) or depression drug prescribing was investigated. OUTCOME MEASURES: Based on the British National Formulary, five main drug chapters constituted a measure of drug counts, with low count as 2 or less and high multidrug count as 3 or more. Key drugs prescribed for COPD, OA and depression were derived from guidelines. RESULTS: The adjusted associations between the comorbid groups and higher multidrug count compared with their respective 'alone' group were: odds ratio (OR) 7.1 (95% CI 5.6 to 9.0) for depression, OR 5.4 (95% CI 4.6 to 6.3) for cardiovascular disease, OR 3.7 (95% CI 2.8 to 5.0) for cerebrovascular disease, OR 3.6 (95% CI 3.1 to 4.3) for OA, OR 3.5 (95% CI 3.0 to 4.2) for diabetes and OR 3.2 (95% CI 2.6 to 4.0) for COPD. In COPD, vascular comorbidity was associated with a significant reduction in key COPD drug treatments (adjusted OR 0.6 (95% CI 0.4 to 0.8). In depression, vascular comorbidity was associated with a reduction in key depression drug treatments (OR 0.6 (95% CI 0.4 to 0.7)). CONCLUSIONS: Our findings show that multidrug prescribing for different body systems is higher with comorbidity and may be associated with lower likelihood of prescribing for specific conditions. Further research is required on whether multidrug prescribing influences the outcomes of care for chronic conditions.