Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease, and clinical and genetic family screening is recommended by guidelines. This study sought to investigate the diagnostic yield of screening relatives of HCM patients and identify predictive factors for HCM development during long-term follow-up in relatives from gene-elusive families. This was a retrospective cohort study of families screened at clinics for inherited cardiomyopathies in Eastern Denmark, from 2006 to2023. We included 1,230 relatives (55% female; age: 42 ± 17 years) from 531 families. The combined clinical and genetic yield at baseline was 26% (n=321). After 7 years (mean) of follow-up (6,762 person-years), 43 (4%) additional relatives developed HCM. The strongest predictors of developing HCM were carrying a likely pathogenic/pathogenic variant (HR: 4.58; 95%CI: 2.50-8.40; P< 0.001) and larger left ventricular maximum wall thickness (MWT) (HR: 2.21 permm; 95%CI: 1.76-2.77 per mm; P< 0.001). In gene-elusive families, we found that an MWT of≥10mm represented the optimal classification threshold for developing HCM (area under the curve: 0.80), with only 2 (0.4%) relatives from gene-elusive families with an MWT of<10mm developing HCM during follow-up. In HCM, the diagnostic yield of a single screening visit was 1 in 4, and the additional yield during 7 years of follow-up was 4%. Gene carriers and relatives from gene-elusive families with a baseline MWT of≥10mm were at the highest risk of developing HCM during follow-up. These findings may inform future recommendations on the management of relatives of HCM patients.