The etiology of the synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome remains unclear. Infectious factors are proposed to be relevant in the etiopathogenesis of the disease. To our knowledge, this is the first reported case of a proposed relationship between Staphylococcus aureus cultured from plantar pustule and SAPHO syndrome, which was successfully treated with co-trimoxazole (CTM) (sulfamethoxazole/trimetoprim). CTM might be the drug of choice for therapy for SAPHO syndrome because of combined antibiotic and immunomodulatory properties. Hypersensitivity testing of the medication in vitro was performed to identify, in the preclinical stage, the hypersensitivity reaction to CTM, which may have been severe.