Background: The epidemiological profile and trends of road traffic injuries (RTIs) in Peru have not been well-defined, though this is a necessary step to address this significant public health problem in Peru. The objective of this study was to determine trends of incidence, mortality, and fatality of RTIs in Peru during 1973-2008, as well as their relationship to population trends such as economic growth. Methods and Findings: Secondary aggregated databases were used to estimate incidence, mortality and fatality rate ratios (IRRs) of RTIs. These estimates were standardized to age groups and sex of the 2008 Peruvian population. Negative binomial regression and cubic spline curves were used for multivariable analysis. During the 35-year period there were 952,668 road traffic victims, injured or killed. The adjusted yearly incidence of RTIs increased by 3.59 (95% CI 2.43-5.31) on average. We did not observe any significant trends in the yearly mortality rate. The total adjusted yearly fatality rate decreased by 0.26 (95% CI 0.15-0.43), while among adults the fatality rate increased by 1.25 (95% CI 1.09-1.43). Models fitted with splines suggest that the incidence follows a bimodal curve and closely followed trends in the gross domestic product (GDP) per capita Conclusions: The significant increasing incidence of RTIs in Peru affirms their growing threat to public health. A substantial improvement of information systems for RTIs is needed to create a more accurate epidemiologic profile of RTIs in Peru. This approach can be of use in other similar low and middle-income settings to inform about the local challenges posed by RTIs. © 2014 Miranda et al.