Background Variation in prescription costs between general practices and within practices over time is poorly understood. Methods From New Zealand's national health data collections, we extracted dispensed medicines data for 1045 general practices in 2011 and 917 practices continuously existing 2008-11. Using indirect standardization to account for patient demographics and morbidity, a standardized prescribing cost ratio (SPR: the ratio of actual: expected prescription costs) was calculated for each practice in each year. Case studies of three outlier clinics explored reasons for their status. Results SPRs ranged from 0.53 to 2.28 (median = 0.98). Of 469 practices with higher than expected costs (SPR > 1.0) in 2011, 204 (43.5%) had a single medicine or therapeutic drug class accounting for >1 5% of total costs. Case studies contrasted practices with overall pharmaceutical expenditure influenced strongly by a few patients needing high-cost medicines, more patients using medicines in one high-cost therapeutic drug class (antiretrovirals), and high medicine use across all therapeutic drug classes. Conclusions Routine data collections can measure inter-practice variation in prescription costs, adjusted for differences in the demography and morbidity profile of each practice's patients. Small groups of patients using high-cost medicines influence general practices' expenditure on pharmaceuticals.