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Introduction Systemic sclerosis (SSc) is an autoimmune disorder that causes vasculopathy and scarring, most commonly in the lungs and skin, but it can also affect 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 significant 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 fibrosis (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), diffusing 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 significantly higher anti-vinculin antibody levels than the control group (P Conclusion Anti-vinculin antibodies in the blood appear to be diagnostic biomarkers for scleroderma. Furthermore, they shed light on some novel perspectives on the pathophysiology of specific lung fibrotic changes. Key Points• This study included two groups of systemic sclerosis patients (PAH-predominant group, ILD-predominant group) as well as a control group to investigate the significance of anti-vinculin antibodies in such cases.• Our results have demonstrated that anti-vinculin antibodies can play a significant role in diagnosing and monitoring systemic sclerosis disease.