Cyclophosphamide is an important immunosuppressive agent in the treatment of many rheumatic diseases. Urticaria and anaphylaxis to intravenous cyclophosphamide (i.v. CYC) have been reported in patients with haematological and solid organ malignancies. This is the first report in the rheumatology literature of a type I hypersensitivity reaction following monthly i.v. CYC. An 18-year-old girl with systemic lupus erythematosus (SLE) developed generalized urticaria (without concomitant angioedema or anaphylaxis) following i.v. CYC. She had previously developed life-threatening angioedema following a respiratory tract infection. She successfully completed regular pulse i.v. CYC with pre-medication with anti-histamine. In the absence of a severe type I hypersensitivity reaction and other suitable immunosuppressive agents, i.v. CYC may be safely continued with pre-medication and careful monitoring during each infusion.