Abstract Objective All health care systems in the world struggle with rising costs for drugs. We sought to explore factors impacting on prescribing costs in a nationwide database of ambulatory care in Germany. Factors identified by this research can be used for adjustment in future profiling efforts. Methods We analysed nationwide prescription data of physicians having contractual relationships with statutory health insurance funds in 2014. Predictor and outcome variables were aggregated at the practice level. We performed analyses separately for primary care and specialties of cardiology, gastroenterology, neurology and psychiatry, pulmology as well as oncology and haematology. Bivariate robust regressions and Spearman rank correlations were computed in order to find meaningful predictors for our outcome variable prescription costs per patient. Results Median age of patients and proportion of DDD issued were substantial predictors for prescription costs per patient in Primary Care, Cardiology, and Pulmology with explained variances between 41 and 61%. In Neurology and Psychiatry only proportion of patients with polypharmacy ≥ 2 quarters was a significant predictor for prescription costs per patient, explaining 20% of the variance. For gastroenterologists, oncologists and haematologists no stable models could be established. Conclusions Any analysis of prescribing behaviour must take the degree into account to which an individual physician or practice is responsible for prescribing patients’ medication. Proportion of prescriptions/DDDs is an essential confounder for future studies of drug prescribing.