BACKGROUND: Polypharmacy, prescription of multiple medications to a patient, is a major challenge for health systems. There have been no peer-reviewed studies of polypharmacy prevalence and medication cost at a population level in England. AIMS: To determine prevalence and medication cost of polypharmacy, by patient characteristics. Design and setting: Retrospective cohort study of North West London electronic health records. METHOD: We quantified prevalence and direct cost of polypharmacy (five or more regular medications), stratified by demographics and frailty. We fitted a mixed-effects logistic regression for polypharmacy. RESULTS: Of 1.7 million adults, 167,665 (9.4%) were on polypharmacy. Age and socio-economic deprivation were associated with polypharmacy (OR 9.24 95% CI 8.99 to 9.50, age 65-74 compared with 18-44; OR 0.68 95% CI 0.65 to 0.71, least deprived compared with most). Polypharmacy prevalence increased with frailty (OR 1.53 95% CI 1.53 to 1.54 per frailty component, for White women). Men had higher odds of polypharmacy than women at average frailty (OR 1.26 95% CI 1.24 to 1.28) and with additional frailty components (OR 1.10 95% CI 1.09 to 1.10). Black people had lower odds of polypharmacy at average frailty (OR 0.82 95% CI 0.79 to 0.85, compared with White), but along with other ethnicities, saw greater odds increases with increasing frailty (OR 1.02 95% CI 1.01 to 1.03). Annual medication cost 8.2 times more for those on polypharmacy compared with not (£370.89 and £45.31). CONCLUSION: Demographic characteristics are associated with polypharmacy, after adjusting for frailty. Further research should explore why, to reduce health inequities and optimise cost associated with polypharmacy.