Background:Type 2 diabetes mellitus is the most common single cause of end-stage renal disease (ESRD), where diabetic nephropathy (DN) is considered the cause in almost half of all patients with ESRD. Despite the availability of many modern therapies for glycemic control, there are no specific curative treatments yet for DN and many diabetic patients still progressed to severe renal damage. Currently, albuminuria is the most commonly used marker to predict onset and progression of DN clinically. However, this traditional marker for DN lacks both sensitivity and specificity to detect early stage of DN. Furthermore, there is a lack of a strong association between albuminuria and glomerular filtration rate (GFR). As such, it is crucial to find earlier and reliable markers for DN diagnosis and intervention providing an opportunity to stop the permanent damage caused by it. Objective: This study focuses on Cyclophilin A (CypA) in urine. CypA is a protein with ubiquitous characteristics, mostly distributed in the cytoplasm and facilitates protein folding and protein trafficking. It has relatively high expression level in normal kidneys. Recently, CypA has been reported to be a reliable novel marker for early diagnosis of DN. Subjects and Methods: Our study was conducted on 90 subjects of comparative age and sex. They were selected from Endocrinology Clinic after written consent at Ain Shams University Hospital and Railway Hospital. Participants were divided into: Group I:  30 healthy control subjects, Group II: 30 T2DM patients without albuminuria (normoalbuminuric), and Group III: 30 T2DM patients with albuminuric DN. Results: Our study showed that regarding the level of urinary CypA there was a highly statistical significant difference between the three groups (F= 221.730, p< 0.01), being higher in GII (normoalbuminuric) (1.69±0.87 ng/ml) than in GI (control) (0.55±0.14 ng/ml)  (t= 7.04, p< 0.01) and higher in GIII (albuminuric DN) (6.01±1.61 ng/ml) than GII (t= 12.93, p< 0.001) and GI (t= 18.55,  p< 0.0001). In addition, we found that urinary CypA was significant higher in GIIIb (macroalbuminuria) (7.23±0.76 ng/ml) than in GIIIa (microalbuminuria) (4.79±1.25 ng/ml) (t= 6.49, p< 0.01). It worth mentioning that, the level of urinary CypA started to increase significantly in stage 2 DN (2.49±0.50 ng/ml) in spite of normal level of albuminuria (no albuminuria) comparing with each of stage 1 DN (1.03±0.15 ng/ml), diabetics with no renal affection (0.99±0.45 ng/ml) and GI (healthy control) (0.55±0.14 ng/ml). There was significant positive correlation between urinary CypA and each of: sCr in GII (r= +0.39, p< 0.05), GIIIa (r= +0.89, p< 0.001) and GIIIb (r= +0.99, p< 0.001) and ACR in GIIIa (r= +0.93, p< 0.001) and GIIIb (r= +0.98, p< 0.001). Conclusion: Our study showed that there was a high significant difference in the level of urinary CypA between diabetic patients with any degree of renal affection and healthy subjects being higher in diabetics with renal affection even without the presence of albuminuria.