Background: As air pollution became a major public health concern, there have been various air quality regulations since 2005 in Seoul metropolitan area, South Korea. However, there are a few studies to evaluate the health effects of these regulations so far. Thus, this study aims to estimate the health effects of the air quality regulations on cause-specific mortality rate (all-cause, cardiovascular, and respiratory mortality rate) in Seoul and Incheon with applying synthetic control method (SCM) to controlled interrupted time series (CITS). Methods: We firstly analyzed the trend of air pollution with descriptive statistics to hypothesize how the intervention would impact on the health effects. Then we constructed synthetic controls (SC) for each cause-specific mortality rate that is made to predict the counterfactual trends of mortality rate in each intervention group. We checked prediction fit of SC with normalized root mean squared error. After selecting well-predicting SC, we finally tested whether the air quality interventions had beneficial effects on cause-specific mortality rate with CITS. Results: We found that the air quality regulations were effective on reducing emission and ambient concentration of PM10. At the stage of SCM, we identified that only the SCs of all-cause mortality rate and cardiovascular mortality rate, not respiratory mortality rate, predicted the counterfactual trend of mortality rate well in both Seoul and Incheon. We found robust evidence that the air quality regulations had beneficial effects on cardiovascular mortality rate in Seoul and Incheon at the stage of CITS. We identified that the regulations prevented monthly deaths due to cardiovascular diseases up to about 14% and 9% in Seoul and Incheon, respectively. Conclusions: With applying SCM to CITS, this study provides additional epidemiologic evidence that the air quality regulations implemented after 2005 in Seoul metropolitan area had beneficial effects on cardiovascular mortality rate in Seoul and Incheon.