Background: Pharmaceutical expenditure growth is a familiar feature in many Western health systems and is a real concern for policymakers. A state funded General Medical Services (GMS) scheme in Ireland experienced an increase in prescription expenditure of 414 % between 1998 and 2012. This paper seeks to explore the rationale for this growth by investigating the composition (Anatomical Therapeutic Chemical (ATC) Group level 1 & 5) and drivers of GMS drug expenditure in Ireland in 2012. Methods: A cross-sectional study was carried out on the Health Service Executive-Primary Care Reimbursement Service (HSE-PCRS) population prescribing database (n = 1,630,775). Three models were applied to test the association between annual expenditure per claimant whilst controlling for age, sex, region, and the pharmacology of the drugs as represented by the main ATC groups. Results: The mean annual cost per claimant was €751 (median = €211; SD = €1323.10; range = €3.27-€298,670). Age, sex, and regions were all significant contributory factors of expenditure, with gender having the greatest impact (β = 0.107). Those aged over 75 (β = 1.195) were the greatest contributors to annual GMS prescribing costs. As regards regions, the South has the greatest cost increasing impact. When the ATC groups were included the impact of gender is diluted by the pharmacology of the products, with cardiovascular prescribing (ATC "C") most influential (β = 1.229) and the explanatory power of the model increased from 40 % to 60 %. Conclusion: Whilst policies aimed at cost containment (co-payment charges; generic substitution; reference pricing; adjustments to GMS eligibility) can be used to curtail expenditure, health promotional programs and educational interventions should be given equal emphasis. Also policies intended to affect physicians' prescribing behaviour include guidelines, information (about price and less expensive alternatives) and feedback, and the use of budgetary restrictions could yield savings in Ireland and can be easily translated to the international context.