Abstract Introduction Cascade genetic screening for familial hypercholesterolemia (FH) is poorly performed when direct contact with relatives by health professionals is not allowed. We aimed to compare the effectiveness of implementing a web-based communication platform in a large-scale cascade genetic screening program for FH, while maintaining the confidentiality of indirect family contacts. Methods The CATCH study is a prospective randomized open-label multicenter implementation trial that promotes family cascade genetic screening in Swiss adults older than 16 years with a newly diagnosed pathogenic variant for FH. Each family was randomly assigned to a multigenerational indirect cascade genetic screening (1:1) either via the possibility to use of a web-based platform designed to send pre-prepared text messages or emails, and allowing to connect to a specialized clinical center, or a cascade genetic screening via the local recommended procedure. The primary outcome was the 6-month participation rate of relatives, defined as the number of genetic tests performed within 6 months after referral, over the number of eligible relatives for screening, i.e. living first-degree relatives aged 5 years or older. The secondary outcome was the 6-month yield of positive genetic tests, defined as the number of positive tests over the number of eligible relatives. Both outcome estimates were obtained after accounting for family clusters. Results Between 11/20 and 12/23, we enrolled 221 adults with a phenotype of FH for genetic testing, with 87 of them having confirmed genetic FH, corresponding to a total of 401 eligible relatives for cascade screening, with 102 relatives eventually undergoing genetic testing. Among the 87 index cases with genetic FH, 44 were randomly assigned to the web-based platform screening, and 43 were assigned to the local procedure screening. The 6-month participation rate of relatives was 71 of the 218 eligible relatives (29% [95% CI 21–38]) for the web-based platform screening, and 31 of the 183 eligible relatives (14% [95% CI 8–23]) for the local procedure screening (odds ratio (OR) 2.46 [95% CI 1.22–4.98]), p=0.012) (Figure). Similarly, the yield of detection of positive relatives was higher for the web-based platform screening, (16% [95% CI 11–23]) compared to the local procedure screening (7% [95% CI 4–13]), with OR of 2.43 [95% CI 1.11–5.30], p=0.026. Among the 55 positive relatives identified with genetic FH within 6-months, 13.0% were younger than 18 years, 25.5% were current smokers, and 56.0% were not using any lipid-lowering drugs. Conclusions The effectiveness of cascade genetic screening for FH was approximately doubled by integrating a web-based platform that facilitates family communication and access to specialized clinical centers. Modern communication technology is well suited to be integrated in large-scale indirect genetic screening programs to increase the early identification of patients at high cardiovascular risk.