Bone involvement is an unusual manifestation of secondary syphilis, but little information is available in the English-language literature. We carried out a systematic review of the English-language literature from 1964 to 2013, describing cases of secondary syphilis with bone involvement. We also describe a case of secondary syphilis with multiple osteolytic lesions, mimicking metastatic cancer or myeloma, which was included in an analysis of 37 eligible cases of secondary syphilis with bone involvement. Of these 37 patients, 28 (76%) patients were male, and the median age was 32 years (range, 12-64 years). Eleven (30%) patients had human immunodeficiency virus (HIV) infection with a median CD4 lymphocyte count of 343 cells/mm (range, 130-689 cells/mm). The diagnosis of early syphilis was suspected based on mucocutaneous findings in 28 (76%) cases. In the remaining 9 (24%) cases, high titers of nontreponemal serologic tests were the only evidence of early syphilis. The median venereal disease research laboratory (VDRL) titer was 1:64 (range, 1:8-1:320), and median rapid plasma reagin (RPR) titer was 1:64 (range, 1:16-1:512). The bones most often affected were long bones of the limbs (n = 22) and skull (n = 21). The bone lesions were multifocal in 27 (73%) cases and osteolytic in 19 (51%) cases. The treatment of syphilitic bone lesions was medical only in most patients, and prognosis was favorable with high-dose penicillin therapy. Clinical features and outcome between HIV-uninfected and HIV-infected patients were not different. Knowledge of this rare entity may lead to early diagnosis and appropriate management.