ObjectivesTo evaluate the prevalence of drink driving and speeding during 2015–2018 in Sao Paulo, Brazil.DesignCross-sectional observational study.SettingRoads representing the five main regions of the city of Sao Paulo in Brazil, one of the world’s largest urban areas.ParticipantsDrivers (N=10 294) stopped at routine roadside breath testing checkpoints and those driving in selected roads for speeding measurement (N=414 664).Primary and secondary outcome measuresMicrowave radar guns were used to measure the speed of vehicles, while the prevalence of drivers under the influence of alcohol was observed in police checkpoints. Data were collected during three consecutive years (2016–2018) following a baseline study established in 2015 using a city-level representative sample of observational data representing all days of the week.ResultsAlcohol-related fatalities kept at a constantly high percentage, with 39% of road traffic deaths involving alcohol in 2016. Drivers testing above the legal breath alcohol concentration limit showed a decreasing trend, from 4.1% (95% CI 2.9% to 5.5%) at baseline to 0.6% (95% CI 0.2% to 1.2%) in the end of 2018 (p<0.001); however, more than half of drivers refused breath tests at checkpoints despite steep legal penalties. The prevalence of speeding among all vehicles decreased from 8.1% (95% CI 7.9% to 8.2%) to 4.9% (95% CI 4.7% to 5.1%) by the end of 2016 (p<0.001), but then increased again to 13.5% (95% CI 13.2% to 13.9%) at the end of the study period (p<0.001).ConclusionsDrink driving rates have reduced, likely due to an increase in drivers refusing breath alcohol tests, while speeding rates have increased significantly by the end of the study period, particularly among motorcycles. Future strategies aiming at reducing road traffic injuries in the major Brazilian city should tailor drink driving and speeding enforcement based on the new evidence provided here.