Out-of-pocket spending on medicines and supplies can lead to a heavy financial burden in households.To determine the out-of-pocket spending on medicines and supplies in Peru and the population groups with the highest out-of-pocket spending on medicines and supplies in 2007 and 2016.We conducted an analytical cross-sectional study of the Peruvian National Household Survey on Living and Poverty Conditions for the years 2007 and 2016. Mean and median out-of-pocket spending on medicines and supplies are reported in USD for the general population, and according to the presence or not of factors described in the literature as associated with out-of-pocket spending on medicines and supplies.92 148 and 130 296 participants from 2007 and 2016 were included. In 2007, a median of 3.19 (interquartile range: 0.96 to 7.99) and an average of 8.14 (95% confidence interval: 7.80 to 8.49) were found for the out-of-pocket spending on medicines and supplies. In 2016, the median and mean out-of-pocket spending on medicines and supplies were 3.55 (interquartile range: 1.48 to 8.88) and 9.68 (95% confidence interval: 9.37 to 9.99), respectively. For 2016, higher out-of-pocket spending on medicines and supplies was found in women, children under five and over 60 years of age, people of higher educational level, having private or armed forces insurance, living in the coastal region, and being in one of the highest per capita quintile of expenditure. Between 2007 and 2016, the out-of-pocket spending on medicines and supplies was significantly increased in children under five (p < 0.001), uninsured persons (p < 0.001), insured to the Seguro Integral de Salud (p < 0.001) or the Armed Forces (p = 0.035), for the urban and rural area (both p < 0.001), and in people without chronic diseases (p < 0.001).An increase in out-of-pocket spending on medicines and supplies was found in the study period. There were population groups with significant increases in out-of-pocket spending on medicines and supplies. It is necessary to explore further the factors associated with out-of-pocket spending on medicines and supplies in groups of greater economic vulnerability regarding direct health spending in Peru.