Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a clinically heterogeneous entity, encompassing a variety of debilitating conditions that have in common inflammation of the skeletal system and skin. To date, there is a paucity of documented efficacious treatment options. We report a 48-year-old man with skeletal and cutaneous signs and symptoms who improved dramatically after treatment with a combination of isotretinoin and pamidronate. This report provides an alternative treatment regimen for SAPHO that addresses the possible underlying pathophysiology of this likely underdiagnosed syndrome.