Treatment with interferon (IFN) could be associated with variable cutaneous adverse reactions. The aim of this study was to describe the clinicopathological spectrum of cutaneous granulomas associated with IFN therapy and identify the causal relation between IFN therapy and granulomatous reactions. The study included 18 patients (16 males and 2 females) with an average age of 48 years. Clinically, most of the lesions were solitary (83.3%) and located on the face (44.4%) and/or trunk (38.9%). The lesions were commonly presented as nodules (33.3%) or plaques (27.8%) with a common size of 5-10 cm. Granulomatous reactions were localized to the injection site in 4 cases, distributed on other body areas (remote granuloma) in 11 cases, and associated with lung involvement (systemic granuloma) in 3 cases. Histologically, injection site granuloma showed suppurative reaction in 75% and sarcoidal reaction in 25%. Remote granuloma showed tuberculoid reaction in 27.3%, interstitial in 27.3%, and sarcoidal in 45.4%. Systemic granuloma showed sarcoidal reaction in all cases. After withdrawal of IFN, only 3 lesions showed spontaneous complete clearance, whereas most of the lesions (83.3%) showed only partial improvement. Our results suggested that IFN is not a causal agent of all associated cutaneous granulomas but it mostly provokes the appearance of granulomatous reactions in susceptible individuals. Findings that prove this concept include the formation of granuloma in body sites away from the injection site, the heterogeneous pattern of granuloma both clinically and histologically, and incomplete clearance of most of the lesions after withdrawal of IFN.