Oral therapies alternative to fluoroquinolones against staphylococcal chronic osteomyelitis have not been evaluated in comparative studies. Consecutive nonaxial Staphylococcus aureus chronic osteomyelitis cases were included in a comparative trial after debridement. Fifty patients were randomized: group A (n = 22) was treated with cloxacillin for 6 weeks intravenously plus 2 weeks orally (p.o.), and group B (n = 28) was treated with rifampin-cotrimoxazole for 8 weeks p.o. During follow-up (10 years), five relapses occurred: two (10%) in group A and three (11%) in group B. Foreign-body maintenance was associated with relapse (P = 0.016). Oral rifampin-cotrimoxazole treatment showed outcomes comparable to those for intravenous cloxacillin treatment.