Leprosy is a chronic granulomatous disease affecting skin and nerves with a range of clinical and immunological responses. The study aimed to identify levels of IL-4 and antibodies to ceramide in the sera of leprosy patients and healthy subjects using enzyme linked immunosorbent assay (ELISA) to evaluate their possible role in disease severity and their correlation to nerve involvement and physical impairments. This study included 25 patients with multibacillary leprosy, 25 with paucibacillary, and 25 healthy controls who were subjected to history taking, clinical examination, and identification of sites and morphology of skin lesions, nerve examination, eye examination, as well as sensory examination. Slit skin smear examination was used for diagnosing paucibacillary (PB) and multibacillary (MB) leprosy cases. Anti-ceramide antibody (ACA) and IL-4 titers were estimated and correlated with the type of leprosy, disease duration, nerve damage, and disabilities. Serum ACA and IL-4 levels were significantly higher in MB than its level in PB leprotic patients and controls. A significant positive correlation was established between nerve affection; physical impairments and serum levels of ACA and IL-4. Levels of ACA and IL-4 can impact nerve affection in leprotic patients and can serve as potential biomarkers of disease progression J Drugs Dermatol. 2022;21(3):284-291. doi:10.36849/JDD.5543.