Objective: 131 patients were recruited at baseline (n = 131) (before initiating steroid therapy); After six weeks of steroid therapy, 91 patients achieved remission (n=91 mean age, 8.96±3.90), whereas 40 were resistant to steroids (n=40, mean age 9.00±3.55). mRNA expression of HDAC2/P-gp and functional analysis of P-gp and enzymatic activity of HDAC2 were analyzed at baseline, at 6 weeks of steroid treatment and at the time of relapse, respectively. Methods: The expression of P-gp on PBMCs were significantly higher in SRNS (11.56±4.56 v/s 4.36±2.15, p<0.001). The mRNA expression of P-gp was significantly lower in SSNS and who achieved remission at 6-weeks of steroid therapy compared to baseline and those who were steroid resistant (n=40,P<0.005). mRNA Expression of HDAC2  was significantly lower in SRNS  (P<0.005) as compared to baseline and those who achieved remission following 6-weeks of steroid therapy. The function of P-gp was significantly lower in NS patients who achieved remission after 6-weeks of steroid therapy as compared to baseline (p<0.005) and SRNS patients (p<0.005). The enzymatic activity of HDAC2 was significantly higher in patients who achieved remission as compared to those who were resistant at 6-weeks of steroid therapy (p<0.005). Results: Expression and function of P-gp and HDAC2 may affect steroid response in NS patients. Combined therapy of steroids with P-gp inhibitor and/or HDAC2 inducers may have rationale in the management of steroid resistant NS patients. Conclusions: Objective: P-glycoprotein (P-gp) over expression in peripheral blood mononuclear cells (PBMCs) has been reported in patients with steroid resistant nephrotic syndrome (NS). Glucocorticoids suppress NFκB-associated co-activator activity by deacetylation of histones by enzyme histone deacetylase (HDAC)-2. Interaction between HDAC2 activity and P-gp expression in childhood NS patients is not clear. To evaluate the role of HDAC2 and P-gp expression on PBMCs and steroid responsiveness in patients with childhood NS.   Methods: 131 patients were recruited at baseline (n = 131) (before initiating steroid therapy); After six weeks of steroid therapy, 91 patients achieved remission (n=91 mean age, 8.96±3.90), whereas 40 were resistant to steroids (n=40, mean age 9.00±3.55). mRNA expression of HDAC2/P-gp and functional analysis of P-gp and enzymatic activity of HDAC2 were analyzed at baseline, at 6 weeks of steroid treatment and at the time of relapse, respectively. Results: The expression of P-gp on PBMCs were significantly higher in SRNS (11.56±4.56 v/s 4.36±2.15, p<0.001). The mRNA expression of P-gp was significantly lower in SSNS and who achieved remission at 6-weeks of steroid therapy compared to baseline and those who were steroid resistant (n=40,P<0.005). mRNA Expression of HDAC2  was significantly lower in SRNS  (P<0.005) as compared to baseline and those who achieved remission following 6-weeks of steroid therapy. The function of P-gp was significantly lower in NS patients who achieved remission after 6-weeks of steroid therapy as compared to baseline (p<0.005) and SRNS patients (p<0.005). The enzymatic activity of HDAC2 was significantly higher in patients who achieved remission as compared to those who were resistant at 6-weeks of steroid therapy (p<0.005). Conclusions: Expression and function of P-gp and HDAC2 may affect steroid response in NS patients. Combined therapy of steroids with P-gp inhibitor and/or HDAC2 inducers may have rationale in the management of steroid resistant NS patients.