Data about lipoprotein changes and their link with cardiovascular disease and atherosclerosis in systemic sclerosis (SSc) are still challenging. We aimed to evaluate serum lipid profile of patients with SSc and to identify potential relation with different disease specific characteristics (clinical, serological, inflammatory tests) in a cross-sectional study. Standard assessments comprised SSc-related parameters (disease subtype, clinical spectrum, immunological tests) and lipid metabolism (total cholesterol and fractions, triglycerides). Impaired lipid profile (low serum HDL- and high LDL-cholesterol, increased serum triglycerides, slightly modification in total cholesterol level) significantly correlated with diffuse SSc, activity (EUSTAR) and severity (MEDSGER), as well as seropositivity for specific antibodies (anti-centromere and anti-topoisomerase 1). The dyslipidemic profile might represent a pathobiological pathway for atherosclerosis in SSc.