Background: Heterozygous familial hypercholesterolemia (HeFH) is under-detected and undertreated. A general practitioner-led screening and care program for HeFH effectively identified and managed patients with HeFH. We evaluated the cost-effectiveness and the return on investment of an enhanced-care strategy for HeFH in primary care in Australia. Methods: We developed a multistate Markov model to estimate the outcomes and costs of a general practitioner-led detection and management strategy for HeFH in primary care compared with the standard of care in Australia. The population comprised individuals aged 50 to 80 years, of which 44% had prior cardiovascular disease. Cardiovascular risk, HeFH prevalence, treatment effects, and acute and chronic health care costs were derived from published sources. The study involved screening for HeFH using a validated data-extraction tool (TARB-Ex), followed by a consultation to improve care. The detection rate of HeFH was 16%, and 74% of the patients achieved target LDL-C (low-density lipoprotein cholesterol). Quality-adjusted life years, health care costs, productivity losses, incremental cost-effectiveness ratio, and return on investment ratio were evaluated, outcomes discounted by 5% annually, adopting a health care and a societal perspective. Results: Over the lifetime horizon, the model estimated a gain of 870 years of life lived and 1033 quality-adjusted life years when the general practitioner-led program was employed compared with standard of care. This resulted in an incremental cost-effectiveness ratio of AU$14 664/quality-adjusted life year gained from a health care perspective. From a societal perspective, this strategy, compared with standard of care was cost-saving, with a return on investment of AU$5.64 per dollar invested. Conclusions: An enhanced general practitioner-led model of care for HeFH is likely to be cost-effective.