Systemic sclerosis, also known as scleroderma, is a complex systemic inflammatory autoimmune disease that targets the vasculature and connective tissue-producing cells and components of the innate and adaptive immune systems. The disease is characterized by a hardening of the skin and an increased synthesis of collagen . Prolidase is a specific imidodipeptidase involved in collagen degradation. The aim of this study was to search the serum prolidase activity (SPA) in the two subtypes of systemic sclerosis: diffuse and limited cutaneous systemic sclerosis. For this purpose, 35 patients diagnosed with systemic sclerosis (24 diffuse and 11 limited) and 41 healthy control subjects were included in the study. SPA was determined using Myara's method, which is a modification of Chinard's method. SPA did not differ between the scleroderma patients and controls (p = 0.467). However, SPA was significantly lower in diffuse form than in both limited form and control subjects (p = 0.021 and p = 0.024, respectively). SPA also did not differ between the limited form and control subjects (p = 0.145). Scleroderma is characterized by excessive deposition of collagen and tissue fibrosis due to the reduced collagen degradation. SPA is reduced in scleroderma patients, especially in diffuse form. Circulating autoantibodies, oxidative stress, and decreased physical activity may contribute to this process.