Background and objective: Frank’s sign is the diagonal ear fold which has been associated with ischemic heart disease. The objective of this work was to evaluate the relationship of Frank’s sign with severity of ischemic heart disease in adults ≤ 65 years old in the northeast of Mexico. Patients and methods: A cross-sectional study was conducted in patients ≤ 65 years old who underwent coronary angiography consecutively over a period of 5 months in 2022. Severe coronary artery disease (CAD) was associated with Frank’s sign and other common cardiovascular risks. To determine the association, bivariate and multivariate analysis was performed using logistic regression that included variables with a value of p < 0.05. Statistical analysis was performed with SPSS version 22. Results: We included 311 patients ≤ 65 years, of whom 80% were men. The median age was 57 years (range 28–65). Frank’s sign was positive in 62% of the population. The main clinical characteristics in patients with Frank’s sign were type 2 diabetes mellitus (55%), p = 0.003, dyslipidemia (53%), p = 0.026 and smoking (68%), p = 0.002. In the multivariate analysis, the independent variables associated with severe CAD were Frank’s Sign OR 3.26; 95% CI (1.98–5.38), p ≤ 0.001, male gender OR 2.28; 95% CI (1.20–4.35), p = 0.012, and dyslipidemia OR 1.81; 95% CI (1.11–2.97), p = 0.017. Conclusions: There is an independent association between Frank’s sign with the presence of severe CAD in patients ≤ 65 years old, which may be useful for screening and prevention.