OBJECTIVES: The aim of this study is to quantify out-of-pocket drug expenditure among ambulatory care users and to identify the variables associated with the payment for medicines during 2010 at the Mexican Institute of Social Security. METHODS: Data from the institutional health survey 2010 was used to estimate the total and mean drug out-of-pocket expenditure among ambulatory care users.  Statistical analysis was performed to test for mean expenditure differences by age and gender. A binary logistic regression model was constructed to identify the main factors related to payment for prescribed medicine. Data was aggregated according to the marginality index estimated by the Mexican National Council of Population to consider socio-economic regional variations. The exchange rate was $12.34 pesos per dollar. RESULTS: A total of 71.9% of the health care users received a prescription for drugs during an out-patient visit and 12.04% reported having paid for the medicine. The total out-of-pocket expenditure in 2010 was USD$134,937. The difference in mean expenditure was statistically significant showing higher expenditure among women compared to men (p-value = 0.0001). Statistical differences were also found across age groups (F-test =16.46); the highest mean expenditure was observed in persons aged 60 years and older, followed by individuals in the age group 51-60 and 0-9 years old. Results from the logistic regression model show that younger men and women are more likely than those in the middle-aged groups to spend on medicine. People living in regions of very high socio-economic marginality spend more on drugs than their better off counterparts. Individuals registered at their family medical care unit are less likely to make expenditures for drugs than the non-registered. Illness increases the probability of drug spending by 0.065. CONCLUSIONS: The out-of-pocket drug expenditure among ambulatory care users varies according to social, economic and demographic factors at the individual and regional levels.