Rationale: Identification of the subpopulation especially susceptible to the adverse effects of second-hand smoke exposure (SHS) would be useful for preventive actions and interventions. Objective: To investigate whether asthmatic heredity indicates susceptibility to the effects of SHS on the risk of adult-onset asthma. Methods: A population-based incident case-control study of clinically defined adult-onset asthma and randomly drawn controls (adults 21-63 years old) from geographically defined area in South Finland. After excluding current and ex-smokers there were 226 cases and 450 disease-free controls. Measurements and Main Results: Our outcome measure was new adult-onset asthma. Parental asthma and recent SHS had synergistic effect on the risk of asthma, the adjusted odds ratio (OR) being 1.97 (95% confidence interval 1.12-3.45) for SHS, 2.64 (1.65-4.24) for parental asthma, and 12.69 (3.44-46.91) for their joint effect (Relative Excess Risk due Interaction (RERI) 9.08 (-0.22- 43.18)). Synergistic effect followed a dose-dependent pattern with both recent and cumulative SHS exposures, with RERI for parental asthma and over 100 SHS cigarette-years of 6.17 (0.57-19.16). Conclusions: This is the first study showing that individuals with asthmatic heredity have a considerably increased risk of adult-onset asthma when exposed to SHS. SHS exposure has dose-dependent synergism with family history of asthma, the joint effect being stronger with higher exposure levels. Avoiding SHS could be an important preventive measure for reducing the risk of adult-onset asthma among those with asthmatic heredity. Asking about family history of asthma is a useful tool for identifying these susceptible individuals in clinical and preventive settings.