Tumour necrosis factor-alpha (TNF-alpha) plays a major role in propagating the inflammatory processes responsible for tissue damage in systemic lupus erythematosus (SLE) and is overexpressed both systemically and locally in this disease. Hence, this pilot study was carried out to assess the safety and efficacy of TNF blockade in patients with active SLE. A total of 46 individuals (27 patients with active SLE and 19 healthy control volunteers) were the subjects of this study. Nine patients with SLE were allocated to treatment arm and 18 were allocated to control arm. In addition to conventional treatment, treatment arm received infliximab infusions 3 mg/kg body weight at 0, 2, 6 weeks and then q 8 weeks for a total of 24 weeks, that is, a total of five doses. Patients were closely monitored for infection. Clinical, laboratory and treatment data were entered into a pre-designed proforma. Health status (SF-36), patient global assessment (PGA) of disease activity, disease activity scores by SLEDAI and organ damage by SLICC/ACR-DI (American College Rheumatology) were measured at baseline and end of the study. Relevant immunological studies included serum levels of TNF-alpha and soluble TNF receptors-1 (p55 srTNF-alpha) and -2 (p75 srTNF-alpha), C3 and C4 complement levels, anti-dsDNA antibody titres (IgM, IgG and IgA isotypes), anti-cardiolipin titres (IgM, IgG and IgA isotypes) and anti-beta2GPI (Glycoprotein I) antibody titres (IgM, IgG and IgA isotypes). Four patients from treatment arm dropped out due to infliximab infusion reaction and 12 patients dropped out from the control arm. The treatment group showed significantly greater improvement in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Improvements in several SF-36 subscales, PGA and VAS-Fatigue (Visual Analogue Scale) were also greater in the treatment group but did not achieve statistical significance. The mean levels of TNF-alpha, soluble TNF receptors-1 (p55 srTNF-alpha) and -2 (p75 srTNF-alpha) were higher in the SLE group compared with the healthy controls but did not change significantly over the study period. We did not face any safety issues with infliximab in this study. In view of improvement in several SLE parameters and good safety profile of infliximab, anti-TNF-alpha therapy is an interesting candidate approach for treating SLE.