Introduction Systemic sclerosis (SSc) is an autoimmune disorder that causes vasculopathy and scarring, most commonly in the lungs and skin, but it can also afect other organs. Endothelial vinculin plays a critical role in angiogenesis regulation. Therefore, vinculin overexpression in SSc may give rise to anti-vinculin antibodies, which may contribute to the development of SSc vasculopathy. The current research aims to (1) determine whether anti-vinculin autoantibodies play a signifcant role in the diagnosis of SSc and (2) compare anti-vinculin serum levels between two scleroderma patient populations, namely, pulmonary artery hypertension (PAH)–predominant and interstitial pulmonary fbrosis (IPF)–predominant groups. Methods This research included 140 participants categorized into three groups: group I—patients with PAH-predominant; group II—patients with ILD-predominant; group III—the control group. Anti-vinculin antibodies were detected in serum samples collected from all participants using ELISA. All subjects underwent high-resolution computed tomography (CT), difusing capacity for carbon monoxide, and pulmonary function tests. Results Patients in group I (PAH-predominant group, N=35) were 41.3 [±11.4] years old, with 80% being women. Patients in group II (ILD-predominant group, N=35) were 41.0 [±11.5] years old. The SSc group showed signifcantly higher antivinculin antibody levels than the control group (P