Synovium and synovial fluid findings in SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome have not been well characterized, and only a few patients have been described in the Americas. We describe clinical, pathologic, and synovial fluid findings in 12 patients with the SAPHO syndrome: hidradenitis suppurativa (7), acne fulminans or conglobata (3), acneiform folliculitis (1) and palmoplantar pustulosis (1). Routine synovial fluid studies were performed in 6 patients, and light and transmission electron microscopic studies were performed in synovium in 2 patients and in bone in 1. The most common musculoskeletal manifestations included erosive or non-erosive oligoarthritis involving metacarpal phalangeal (MCP) and metatarsal phalangeal (MTP) joints as seen in 9 patients, sclerosis of the sacroiliac joints as seen in 5 patients, and osteitis pubis as seen in 1. Three patients had signs of skeletal hyperostosis. The patients with acne fulminans and acneiform folliculitis had chronic aseptic multifocal osteomyelitis. Synovial fluid was sterile in 7, mildly inflammatory in 5, and highly inflammatory in 2. Electron microscopic studies of synovium in 2 patients and of bone in 1 were not useful to detect microorganisms. Three African-American patients with hidradenitis suppurativa presented with pyoderma gangrenosum, and 2 of them had leukocytoclastic vasculitis, and a life threatening course unresponsive to antibiotics, corticosteroids and immunosuppressive therapy. SAPHO in the Americas is most severe in African-Americans with hidradenitis suppurativa, and it presents with heterogeneous musculoskeletal and cutaneous manifestations including erosive polyarthritis or oligoarthritis with nonspecific mild inflammatory fluid. Leukocytoclastic vasculitis and recalcitrant pyoderma gangrenosum were seen in 2 of our patients with the most severe hidradenitis suppurativa. SAPHO syndrome may present with clinical manifestations similar to those seen with seronegative spondyloarthropathies, but it has distinctive cutaneous, radiographic articular, and bone manifestations. Sites of chronic infection need aggressive antibiotic therapy and may need surgical resection.