The cutaneous manifestations of secondary syphilis can vary significantly between patients, leading to a more difficult or delayed diagnosis. Here we present an instructive case of secondary syphilis in a 45-yearold, HIV-positive male patient. He presented with a solitary, crusted anterior neck nodule without concomitant systemic symptoms. Together, history and physical exam were concerning for non-melanoma skin cancer. Histopathologic evaluation of the lesion revealed an extensive infiltrate of plasma cells at the dermoepidermal junction, and immunohistochemical staining revealed numerous Treponema pallidum microorganisms. Physicians must keep syphilis in the differential diagnosis when evaluating atypical nodular lesions resembling non-melanoma skin cancer for the purpose of initiating appropriate antibiotic treatment and preventing future infectious complications.