Little is known about recent nonmedical prescription tranquilizer and stimulant use trends in Latin America. We tested whether recent trends among students in three South American countries differed by sex over time.Three countries independently collected National School Students Survey on Drugs. Students in 8th, 10th, and 12th grades were sampled in Argentina (2007-2014, N = 328,202), Chile (2007-2015, N = 136,379), and Uruguay (2007-2016, N = 32,371). Weighted linear regression models predicted the prevalences and trends over time of past-year nonmedical tranquilizer and stimulant use by country, and tested whether trends differed by sex, adjusting for school type and grade.In Argentina from 2007 to 2014, past-year nonmedical prescription tranquilizer (girls: 2.8 to 2.6%, boys: 2.5 to 2.3%) and stimulant (girls: 1.7 to 1.3%, boys: 1.9 to 1.5%) use trends did not differ by sex. In Chile from 2007 to 2015, nonmedical prescription tranquilizer use trends significantly differed comparing girls (3.9 to 10%) with boys (3.2 to 6.9%); stimulant use trends did not differ comparing girls (1.6 to 2.0%) with boys (2.0 to 1.3%). In Uruguay from 2007 to 2014 and 2014-2016, past-year nonmedical prescription tranquilizer (girls: 5.1 to 6.6%; boys: 2.8 to 4.2%) and stimulant (girls: 1.8 to 0.7%; boys: 1.8 to 0.7%) use trends did not differ by sex.Trends of nonmedical prescription tranquilizer use recently increased in Chile and Uruguay, widening by sex over time in Chile only. The drivers of increasing tranquilizer use among girls in Chile and Uruguay merit further investigation.