Exposure to fine particles in wildfire smoke is deleterious for human health and can increase cases of cardio-respiratory illnesses and related hospitalizations. Neighborhood-level risk factors can increase susceptibility to environmental hazards, such as air pollution from smoke, and the same exposure can lead to different health effects across populations. While the San Diego-Tijuana border can be exposed to the same wildfire smoke event, socio-demographic differences may drive differential effects on population health. We used the October 2007 wildfires, one the most devastating wildfire events in Southern California that brought smoke to the entire region, as a natural experiment to understand the differential effect of wildfire smoke on both sides of the border. We applied synthetic control methods to evaluate the effects of wildfire smoke on cardio-respiratory hospitalizations in the Municipality of Tijuana and San Diego County separately. During the study period (October 11th- October 26th, 2007), 2009 hospital admissions for cardio-respiratory diseases occurred in San Diego County while 37 hospital admissions were reported in the Municipality of Tijuana. The number of cases in Tijuana was much lower than San Diego, and a precise effect of wildfire smoke was detected in San Diego but not in Tijuana. However, social drivers can increase susceptibility to environmental hazards; the poverty rate in Tijuana is more than three times that of San Diego. Socio-demographics are important in modulating the effects of wildfire smoke and can be potentially useful in developing a concerted regional effort to protect populations on both sides of the border from the adverse health effects of wildfire smoke.