Infection remains a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). To describe the nature and outcomes of infection and determine their associated risk factors in patients with SLE, we performed a nested case-control study at the University of Toronto Lupus Clinic, with prospective follow-up according to a standard protocol since 1970. Cases were SLE patients seen between January 1987 and January 1992 who had documented infections and controls were patients without infection from the same cohort matched for age, gender and time of visit. The type, site and outcome of infection were recorded for each case. A conditional logistic regression analysis was performed to compare factors associated with infection in cases and their controls. Ninety-three patients had 148 infection episodes; the majority were bacterial, but viral, fungal and protozoan organisms were also identified (multiple organisms in seven). Forty-eight patients required hospital admission and three patients died. Steroids at time of infection, as well as use ever, duration and dose, immunosuppressives at time of infection and use ever, active renal disease, CNS damage, SLEDAI at the time of infection, adjusted mean SLEDAI and variability measure were significantly associated with infection by univariate analysis. By multivariate analysis one factor remained statistically significant: use of steroids ever (P = 0.029). Infection carries a large burden for SLE patients. Until new medications which will control disease activity without predisposing to infection are developed, careful titration of steroids and cytotoxic drugs to control disease activity will remain crucial.