Systemic Lupus Erythrematosus (SLE) is an inflammatory autoimmune disorder that may affect multiple organ systems. The clinical course is marked by spontaneous remission and relapses. Severity may vary from mild episodic disorder to a rapidly fulminant life threatening illness. Clinical manifestations of Lupus Nephritis (LN) are varied according to the renal pathologic lesions. Treatment of LN remains controversial. As a chronic disease with periods of remission and relapses, it is unclear whether relapses should be treated as the initial presentation of the disease. This prospective study was designed to compare between three different modalities of therapy for treating LN patients. The study includes all systemic lupus patients seen in Alexandria University Hospital since January 2004 for 6 months. Forty-three patients with SLE were presented to us by SLE, only 31 had LN and 22 were included in the study. The patients were classified randomly into 3 arms. All patients received steroid therapy plus from the beginning either Cyclophosphamide (CYP) [Group I, n=7], or Cyclosporine (CsA) [Group II, n=7], or Azathioprine (AZA) [Group III, n=8], Full history and examination were done. Laboratory investigations included routine and immunological studies of ANA, Anti-DNA, C3 and C4. Renal biopsy was done in all patients. After 6 months of follow up; Serum creatinine was stationary in CYP group from 2.2 +/- 1.1 to 2.1 +/- 1.7; while significantly decreased in CsA from 2.8+1.7 to 1.0 +/- 0.5 mg/dl. Moreover; while proteinuria decreased in CYP from 2.7 +/- 0.7 to 1.8 +/- 2.2; there was more pronounced decreased from 6.9 +/- 10.0 to 2.4 +/- 1.2 g/24 hr in CsA group despite very huge increase in glomerular filtration rate (GFR). 2 out 7 cases of CsA group; while 2 of 6 of CYP group did not show improvement. Moreover; 3 of 6 of CYP group and 1 of 6 of AZA group needed to be shifted to CsA group because of side effects and/or no response to CYP and showed good response. These patients were either class V or IV. However; only one case in this study with signs of acute CsA toxicity was reversed by monitoring the dose. In conclusion, CsA in this study proved to be superior over CYP in LN at least in the short term follow up; provided to be given with appropriate doses even if it is used in class IV, which was thought to be very responsive to CYP.