<p><b>BACKGROUND: </b>Hereditary transthyretin amyloid cardiomyopathy is commonly caused by the Val122Ile variant, a mutation found in non-Hispanic individuals of West African descent but understudied among the Hispanic/Latino (H/L) population, despite their admixed genetic ancestry (African ancestry [AA], European ancestry [EA], and Amerindian ancestry) and heterogeneous AA proportions within disaggregated backgrounds.</p><p><b>OBJECTIVES: </b>This study aimed to determine Val122Ile variant prevalence among community-dwelling H/L adults and disaggregated background groups; to evaluate associations with genetic continental ancestry; and to characterize echocardiographic phenotype.</p><p><b>METHODS: </b>We analyzed cross-sectional data from 12,687 H/L adults (aged 18-74) in the Hispanic Community Health Study/Study of Latinos cohort (2008-2011), who consented to genome-wide studies and continental ancestry ascertainment. Echocardiograms were analyzed among 6,376 Hispanics/Latinos ≥44 years. Complex survey analysis, logistic regression, and survey weights were employed.</p><p><b>RESULTS: </b>In the HCHS/SOL (Hispanic Community Health Study/Study of Latinos), 0.82% of H/Ls carried the Val122Ile variant. H/Ls of Dominican descent had the highest Val122Ile variant prevalence (2.60%) compared to other background groups. Even though Val122Ile carriers had a higher fraction of AA than noncarriers (0.38 vs 0.15, P < 0.0001), their highest fraction of continental ancestry was EA (0.42 ± 0.04). A 1% increase in AA raised Val122Ile variant odds by 4% (OR: 1.04; 95% CI: 1.03-1.06), while a 1% increase in EA or Amerindian ancestry lowered the odds by 3% (OR: 0.97; 95% CI: 0.96-0.99) and 2% (OR: 0.98; 95% CI: 0.97-0.99), respectively. No differences were observed in the echocardiographic phenotype of Val122Ile carriers vs noncarriers.</p><p><b>CONCLUSIONS: </b>The Val122Ile variant prevalence varied depending on AA proportions among H/Ls and was seen more commonly among Dominicans, highlighting opportunities for preventative hereditary transthyretin amyloid cardiomyopathy screening.</p>