Background: Cost-effectiveness analyses provide insight in the use of lifestyle interventions. To evaluate the cost-effectiveness of a lifestyle intervention compared to usual care in people with Familial Hypercholesterolemia, 340 people with FH were randomized to the intervention or control group. LDL cholesterol, quality of life and costs were measured at 0 and 12 months. Cost-effectiveness analyses were performed from a healthcare perspective using bootstrapping techniques. Results: Non-significant decreases in LDL cholesterol and quality of life were found. The mean between-group difference in costs was €-237 (95% CI -1,386 to 130). The incremental cost-effectiveness ratios were 1,729 per 1 mmol/l LDL cholesterol and 145,899 per QALY gained. Assumed that the small non-significant decrease in LDL cholesterol is attributed to the intervention, the probability of cost-effectiveness of the intervention compared to usual care was 91% per 1 mmol/l LDL cholesterol reduction and 75% per QALY gained at a ceiling ratio of €20,000. Conclusions: The intervention is not cost-effective. Trial registration: NTR1899, date 07-07-2009.