Heat shock protein 27 (Hsp27) is over-expressed after cells exposure to stressful conditions that include oxidative stress like diabetes as well as chronic kidney disease. Here, the serum Hsp27 levels in Egyptian type 2 diabetic subjects with and without diabetic nephropathy (DN) were investigated. Serum Hsp27 levels were determined using The AssayMax Human Hsp27 ELISA kit in 72 individuals: 14 diabetic control subjects, 28 diabetic subjects with hypertension and/or dyslipidemia as risk factors for DN and 30 individuals with different DN stages (DN1= 6, DN2= 9 and DN3= 15 patients) according to the estimated glomeular filtration rate. Serum Hsp27 concentrations were significantly higher in patients at risk to and with DN compared to diabetic control subjects (p<0.01). Moreover, before microalbuminuria becomes evident, serum Hsp27 levels showed higher sensitivity and area under the curve compared to common traditional markers for diagnosis of DN as creatinine and microalbuminuria. In conclusion, our results showed, for the first time, that serum Hsp27 concentrations appear to be related to the incidence of DN as a microvascular complication in patients with type 2 diabetes mellitus and we concluded that serum HSP 27 may be used as an early marker for diagnosis of diabetic nephropathy.