The treatment of salmonella osteomyelitis in sickle cell disease (SCD) is difficult and the emergence of antibiotic resistance in Salmonella spp presents further problems for clinicians treating SCD. Three patients presented with salmonella bacteraemia. Treatment with several intravenous antibiotics did not prevent the subsequent development of osteomyelitis. Emergence of resistance to multiple antibiotics, including ciprofloxacin, during the treatment of salmonella osteomyelitis in SCD patients is reported here for the first time. Ceftriaxone 2 g once daily given for 3 months to 3 years was an effective and convenient treatment for osteomyelitis caused by multiply-resistant salmonella. Two of these patients gave a definite history of diarrhoea, and stool cultures confirmed the presence of Salmonella spp in one. Our experience shows that salmonella osteomyelitis may not be prevented by early treatment of bacteraemia in SCD patients. Other measures to reduce the risk of salmonella infection are therefore necessary.