Background: In view of rapidly increasing prescription costs, case-mix adjustment should be considered for effective control of costs. We have estimated the variability in pharmacy costs explained by ACG in centers using patient electronic records, profiled centers and physicians and analyzed the correlation between cost and quality of prescription. Methods: We analyzed 65,630 patient records attending five primary care centers in Spain during 2005. Variables explored were age, gender, registered diagnosed episodes of care during 2005, total cost of prescriptions, physician and center. One ACG was assigned to each patient with ACG case-mix software version 7.1. In a two-part model, logistic regression was used to explain the incurrence of drug expenditure at the first stage and a linear mixed model that considered the multilevel structure of data modeled the cost, conditional upon incurring any expense. Risk and efficiency indexes in pharmacy cost adjusted for ACG were obtained for centers and physicians. Spearman rank correlation between physician expenditure, adjusted for ACG, and a prescription quality index was also obtained. Pediatric and adult data were analyzed separately. Results: No prescription was recorded for 13% of adults and 39.6% of children. The proportion of variance of the incurrence of expenditure explained by ACGs was 0.29 in adults and 0.21 in children. For adults with prescriptions, the variance of cost explained by ACGs was 35.4%, by physician-center was 1.8% and age 10.5% (residual 52.3%). For children, ACGs explained 22.4% of cost and physician-center 10.9% (residual 66.7%). Center efficiency index for adults ranged 0.58 to 1.22 and for children 0.32 to 2.36. Spearman correlation between expenditure and prescription quality index was -0.36 in family physicians (p = 0.019, N = 41) and -0.52 in pediatricians (p = 0.08, N = 12). Conclusion: In our setting, ACG is the variable studied that explains more variability in pharmacy cost in adults compared to physician and center. In children there is greater variability among physicians and centers not related to case-mix. In our sites, ACG is useful to profile physicians and centers using electronic records in real practical conditions. Physicians with lower pharmaceutical expenditure have higher scores for a prescription quality index.