<p>Previous studies have demonstrated that cathepsin B is up-regulated in the myocardium of both mice and humans with pathological cardiac hypertrophy. However, it remains unknown whether cathepsin B is detectable in human peripheral blood lymphocytes (PBLs) and whether its expression is associated with pathological hypertrophy. In this study, immunofluorescence staining confirmed the presence of cathepsin B in human PBLs. Western blotting analysis and correlation studies further revealed a positive correlation between cathepsin B protein levels in PBLs and that in cardiac tissues (<i>r</i> = 0.441, <i>p</i> = 0.017). We also investigated the association between cathepsin B expression level in PBLs and cardiac structure and function. Quantitative PCR and western blotting analyses indicated that patients with left ventricular hypertrophy, particularly those with eccentric hypertrophy, exhibited significantly elevated cathepsin B expression in PBLs (<i>p</i> &lt; 0.001). Logistic regression analysis identified cathepsin B as an independent risk factor for left ventricular hypertrophy (odds ratio = 4.863, 95% confidence interval: 1.341–17.632). Receiver operating characteristic analysis further supported its diagnostic value (area under the curve = 0.748, <i>p</i> = 0.001). In summary, cathepsin B levels in PBLs positively correlates with myocardial levels and may serve as a peripheral biomarker for diagnosing maladaptive cardiac hypertrophy.</p>