Most of urban air quality studies focus on the megacities of North America, Europe and, recently, Asia. Meanwhile, the most polluted urban areas in the world are rapidly growing large, mid-size and small cities of Asia, Middle East, Africa and South America. This raises a question: why relatively smaller cities are more polluted than the megacities? This study presents the first comprehensive decade-long analysis of the effects of fuel and transport regulations on PM2.5 (particulate matter of aerodynamic diameter <2.5 mm) pollution in Quito, a medium-size city of South America. The effectiveness of a number of regulations is quantified through the elaboration of a high accuracy (98%) regression model. The model estimated that the PM2.5 concentrations were reduced by 67.6 mg/m3, combating the effect of city growth and intense motorization, reducing the annual PM2.5 concentrations to 17.4 mg/m3. This study is recommended as a guideline for thousands of other cities worldwide looking for optimal urban particulate pollution management.