Ground-based and airborne volatile organic compound (VOC) measurements in Los Angeles, California, and Paris, France, during the Research at the Nexus of Air Quality and Climate Change (CalNex) and Megacities: Emissions, Urban, Regional and Global Atmospheric Pollution and Climate Effects, and Integrated Tools for Assessment and Mitigation (MEGAPOLI) campaigns, respectively, are used to examine the spatial variability of the composition of anthropogenic VOC urban emissions and to evaluate regional emission inventories. Two independent methods that take into account the effect of chemistry were used to determine the emission ratios of anthropogenic VOCs (including anthropogenic isoprene and oxygenated VOCs) over carbon monoxide (CO) and acetylene. Emission ratios from both methods agree within ±20%, showing the reliability of our approach. Emission ratios for alkenes, alkanes, and benzene are fairly similar between Los Angeles and Paris, whereas the emission ratios for C7–C9 aromatics in Paris are higher than in Los Angeles and other French and European Union urban areas by a factor of 2–3. The results suggest that the emissions of gasoline-powered vehicles still dominate the hydrocarbon distribution in northern mid-latitude urban areas, which disagrees with emission inventories. However, regional characteristics like the gasoline composition could affect the composition of hydrocarbon emissions. The observed emission ratios show large discrepancies by a factor of 2–4 (alkanes and oxygenated VOC) with the ones derived from four reference emission databases. A bias in CO emissions was also evident for both megacities. Nevertheless, the difference between measurements and inventory in terms of the overall OH reactivity is, in general, lower than 40%, and the potential to form secondary organic aerosols (SOA) agrees within 30% when considering volatile organic emissions as the main SOA precursors.