All patients with moderate-to-severe SLE will be considered for this trial, including women and minorities. SLE is too rare a disease in children for it to be feasible to include them. Patients must meet the following criteria to be eligible for participation in this clinical trial:

• Four or more ACR criteria (90), as revised by Hochberg (91) for the classification of SLE.
• Involvement of one or more of the following organ systems (renal, neurologic, hematologic, cardiac, pulmonary, cutaneous, gastrointestinal) of moderate-to-severe severity as indicated by an "A" score on the BILAG, a "2" or "3" for severity on SLAM, or severe enough to require hospitalization if the organ involvement was not "captured" on either the BILAG or SLAM instruments.
• A lack of response to daily corticosteroids in moderate-to-high doses (0.5 -1 mg prednisone/kg/day or equivalent anti-inflammatory dose of methyprednisolone, dexamethasone, or triamicinolone). When cyclophosphamide is the accepted standard of care (renal and neurologic), the maximally tolerated dose of prednisone will be sufficient to meet the corticosteroid criterion. The ideal body weight will be used for this criterion in patients who are morbidly obese. The equivalent dose of triamcinolone (4mg triamcinolone=5mg prednisone) can be used to meet the criterion.

And/or:

• A lack of response to IV pulse corticosteroids (1 gram methylprednisolone or 180 mg dexamethasone).
• Duration of treatment to determine lack of response is 3 days or longer for neurologic, renal, hematologic, pulmonary, or cardiac lupus, one month or longer for serositis.

And/or:

• Equivalent degree of immunosuppression with azathioprine, methotrexate, cyclosporin, or mycophenolate mofetil. Equivalent degrees of immunosuppression are: azathioprine - 100 mg daily or more; methotrexate - 7.5 mg weekly or more; cyclosporin - 150 mg daily or more; mycophenolate mofetil - 1000 mg daily or more. Duration to determine lack of response should be one month or longer.

And/or:

• Appropriate other treatment (such as intravenous immunoglobulin for hemolytic anemia and thrombocytopenia).
• SLE patients seeking treatment for neurological complaints will be evaluated by a neurologist to concur that the patient meets eligibility criteria.
• Appropriate other treatment for cutaneous lupus patients may include combination antimalarial drugs (such as the combination of hydroxychloroquine or chloroquine with quinacrine).
• Patients may enter the trial if they received one dose of IV cyclophosphamide to "temporize" or "stablize" them prior to screening visit or after signing consent or if previous IV cyclophosphamide was for a PAST organ system, and patient presents with NEW organ system requiring IV cyclophosphamide.
• Insurance or other source of funds to pay for expenses related to this trial.

Exlcusion Criteria:

• Age less than 18 years and over 70 years.
• Any risk of pregnancy - ALL female patients must have an effective means of birth control or be infertile due to hysterectomy, fallopian tube surgery, or menopause.
• Previous completion of the NIH IV cyclophosphamide protocol.
• Cardiac ejection fraction < 45%.
• Serum creatinine > 3.0 mg/dL.
• FVC or FEV < 50% predicted.
• Bilirubin > 2.0, transaminases > 2x normal.
• Patients who are preterminal or moribund.
• SLE patients presenting with arthritis for entry organ system.