This study compares and explains differences in perceptions of cardiovascular disease (CVD) risk and preventive behaviors in people with and without a known genetic predisposition to CVD. A cross-sectional study using two samples was performed. The first sample (genetic predisposition; n = 51) consisted of individuals recently diagnosed with familial hypercholesterolemia (FH) through DNA testing. The second sample (no genetic predisposition; n = 49) was recruited among patients with CVD-risk profiles based on family history of CVD, cholesterol levels, and blood pressure, registered at general practices. Participants filled out a postal questionnaire asking about their perceived risk, causal attributions (i.e. genetic and lifestyle), and about perceived efficacy and adoption of preventive behavior (i.e. medication adherence and adoption of a healthy diet and being sufficiently active). Perceived comparative risk, genetic attributions of CVD, and perceived efficacy of medication were higher in the "genetic predisposition" sample than in the "no genetic predisposition" sample. The samples did not differ on lifestyle attributions, efficacy of a healthy lifestyle, or preventive behavior. Individual differences in perceived risk, genetic attributions, perceived efficacy of medication, and adoption of a healthy lifestyle were best explained by family history of CVD. Our findings suggest that in people diagnosed with a single gene disorder characterized by a family disease history such as FH, family disease history may be more important than DNA information in explaining perceptions of and responses to risk.