A knowledge of the causes and risk factors of fatal infection in childhood lupus nephritis (LN) patients treated with intravenous cyclophosphamide (IVCY) is important to enable optimal treatment. During an 11-year period (1996-2007), severe infection cases occurred in 31/84 (36.9%) patients with 64 infection episodes in our central referral institution in southern Thailand. Fatal infections occurred in 13/31 (41.9%) patients, most (11/13, 84.6%) during the first infective episode. The major causative organisms of the fatal infections were fungus and Gram-negative bacilli. Fatal infections were more likely to occur in patients with a prior history of treatment with pulse methylprednisolone and in patients with more active LN, as evidenced by the higher proteinuria and serum creatinine levels and lower hemoglobin and lymphocyte counts in this group than in patients with non-fatal infections. Multivariate analysis indicated that factors associated with fatal infection were prior treatment with pulse methylprednisolone [odds ratio (OR) 11.2, 95% confidence interval (CI) 1.9-61.0], renal failure (OR 5.9, 95% CI 1.0-34.8), and fungal infection (OR 23.9, 95% CI 1.9-298.2). Cases of active LN treated with IVCY and pulse methylprednisolone who later develop severe infection that fails to respond to antibiotics should be carefully investigated for fungal infection.