Abstract Objective To investigate potential interactive effects of fine particulate matter (PM 2.5 ) and ozone (O 3 ) on daily mortality at global level. Design Two stage time series analysis. Setting 372 cities across 19 countries and regions. Population Daily counts of deaths from all causes, cardiovascular disease, and respiratory disease. Main outcome measure Daily mortality data during 1994-2020. Stratified analyses by co-pollutant exposures and synergy index (>1 denotes the combined effect of pollutants is greater than individual effects) were applied to explore the interaction between PM 2.5 and O 3 in association with mortality. Results During the study period across the 372 cities, 19.3 million deaths were attributable to all causes, 5.3 million to cardiovascular disease, and 1.9 million to respiratory disease. The risk of total mortality for a 10 μg/m 3 increment in PM 2.5 (lag 0-1 days) ranged from 0.47% (95% confidence interval 0.26% to 0.67%) to 1.25% (1.02% to 1.48%) from the lowest to highest fourths of O 3 concentration; and for a 10 μg/m 3 increase in O 3 ranged from 0.04% (−0.09% to 0.16%) to 0.29% (0.18% to 0.39%) from the lowest to highest fourths of PM 2.5 concentration, with significant differences between strata (P for interaction <0.001). A significant synergistic interaction was also identified between PM 2.5 and O 3 for total mortality, with a synergy index of 1.93 (95% confidence interval 1.47 to 3.34). Subgroup analyses showed that interactions between PM 2.5 and O 3 on all three mortality endpoints were more prominent in high latitude regions and during cold seasons. Conclusion The findings of this study suggest a synergistic effect of PM 2.5 and O 3 on total, cardiovascular, and respiratory mortality, indicating the benefit of coordinated control strategies for both pollutants.