Both linezolid and cotrimoxazole are antibiotics that are well suited for oral therapy of bone and joint infections (BJI) caused by otherwise resistant Gram-positive cocci (GPC) (resistance to fluoroquinolones, maccolides, betalactamines). However, in this context, no data are currently available regarding the safety and tolerance of these antibiotics in combination with rifampicin. The objective of this study was to compare the efficacy and safety of a combination of rifampicin and linezolid (RLC) with those of a combination of rifampicin and cotrimoxazole (RCC) in the treatment of BJI. Between February 2002 and December 2006, 56 adult patients (RLC, n = 28; RCC, n = 28), including 36 with infected orthopaedic devices (RLC, n = 18; RCC, n = 18) and 20 with chronic osteomyelitis (RLC, n = 10; RCC, n = 10), were found to be eligible for inclusion in this study. Patients who discontinued antibiotic therapy within 4 weeks of commencing treatment were considered to represent cases of treatment failure and were excluded. Rates of occurrence of adverse effects were similar in the two groups, at 42.9% in the RLC group and 46.4% in the RCC group (p = 1.00), and led to treatment discontinuation in four (14.3%) RLC and six (21.4%) RCC patients. Cure rates were found to be similar in the two groups (RLC, 89.3%, RCC, 78.6%; p = 0.47). Prolonged oral RLC and RCC therapy were found to be equally effective in treating patients with BJI caused by resistant GPC, including patients with infected orthopaedic devices. However, the lower cost of cotrimoxazole compared with linezolid renders RCC an attractive treatment alternative to RLC. Further larger clinical studies are warranted to confirm these preliminary results.