Since the efficacy of β-lactams against pathogens such as methicillin-susceptible Staphylococcus aureus (MSSA) is related to the time for which serum drug concentrations exceed the MIC for the pathogen, administration of anti-staphylococcal β-lactams by continuous infusion may provide a more suitable means of drug delivery than intermittent dosing. To assess the clinical efficacy of continuous-infusion therapy, we reviewed the outcomes for 20 consecutive patients with proven serious MSSA sepsis (three with endocarditis, ten osteomyelitis, one endocarditis plus osteomyelitis and six deep abscess) treated with continuous-infusion flucloxacillin (6-12 g/day). Patients initially receiving routine intermittent-dose flucloxacillin therapy were changed to continuous-infusion flucloxacillin (mean duration 29 days; range 4-60 days) for completion of their treatment course. In the majority of cases this was given at home. Serum flucloxacillin concentrations during continuous-infusion flucloxacillin 12 g/day were 11.5-> 40 mg/L (ten patients) and those during continuous-infusion flucloxacillin 8 g/day were 8-> 40 mg/L (five patients), these concentrations being well above the expected MIC of flucloxacillin for MSSA. Continuous-infusion flucloxacillin was well tolerated by most patients, and 14/17 patients (82%) who completed their course of continuous-infusion flucloxacillin were judged clinically and microbiologically cured at long-term follow-up (mean 67 weeks; range 4-152 weeks). These preliminary data suggest that, following initial intermittent-dose flucloxacillin therapy, continuous-infusion flucloxacillin is an effective treatment option for serious MSSA sepsis, and forms a feasible and possibly preferable alternative to glycopeptides when considering home-based parenteral therapy for these infections. Further studies are needed to identify whether continuous-infusion flucloxacillin can entirely replace intermittent-dose therapy for such infections.