A granulomatous tissue response may be observed in untreated, long-standing lesions of secondary syphilis. In addition to poorly defined granulomatous inflammation, leprosy-like sarcoidal and palisaded granulomatous inflammation has been documented in literature reports of lues. Herein, we report a 47-year-old man who presented with a 3-month history of a generalized non-pruritic macular and papular rash located on the trunk and extremities. Histopathologically, there was an interstitial arrangement of histiocytes with occasional multinucleated giant cells positioned among collagen bundles without associated necrosis, thereby closely mimicking interstitial granuloma annulare. A clue to the diagnosis was the presence of admixed plasma cells. To the best of our knowledge, this is the first reported case of secondary syphilis showing an interstitial granulomatous pattern mimicking interstitial granuloma annulare.