ObjectiveTo assess the relapse rate， clinical efficacy， and safety of a traditional Chinese medicine （TCM） sequential syndrome differentiation protocol for frequently relapsing/steroid-dependent nephrotic syndrome （FRNS/SDNS） in children. MethodsA total of 151 children with FRNS/SDNS treated in the First Affiliated Hospital of Henan University of Chinese Medicine from December 2020 to June 2024 were randomized into an observation group （77 cases） and a control group （74 cases）. Both groups received Western medicine （prednisone tablets and tacrolimus capsules）. In addition， the observation group additionally underwent TCM sequential syndrome differentiation and the control group received 1/10 of the TCM dose. The 6-month intervention was followed by a 12-month follow-up， totaling 18 months of observation across seven time points （before treatment and after 1， 2， 4， 24， 52， 76 weeks of treatment）. The evaluation was carried out based on the following indicators. ① The relapse rates were mainly recorded after 24， 52， 76 weeks of treatment. ② The efficacy was evaluated based on the clinical remission rates after 1， 2， 4 weeks of treatment， the time to proteinuria clearance， the levels of 24-hour urine total protein （24-h UTP）， serum total protein （TP）， serum albumin （ALB）， cholesterol （CHO）， and triglycerides （TG） and the TCM symptom scores before treatment and after 24 weeks of treatment. ③ The treatment safety was evaluated based on blood routine and levels of liver enzymes， renal function indicators and blood glucose （Glu） before treatment and after 24 weeks of treatment. Results① Relapse rate： After 24 weeks of treatment， no significant difference in relapse rate was found between the two groups. The observation group showed lower relapse rates than the control group after 52 weeks of treatment ［24.2% （16/66） vs. 52.5% （31/59）， χ²=10.634， P<0.01］ and 76 weeks of treatment ［42.4% （28/66） vs. 74.6% （44/59）， χ²=13.186， P<0.01］ than the control group. ② Efficacy indicators： The two groups showed no significant difference in remission rate after 1 week of treatment. The observation group demonstrated higher remission rates after 2 weeks of treatment ［88.2% （67/76） vs. 74.0% （54/73）， Z=-1.999， P<0.05］ and 4 weeks of treatment ［94.7% （72/76） vs. 82.2% （60/73）， Z=-2.3589， P<0.05）. In addition， the observation group had shorter time to proteinuria clearance （P<0.01）. After treatment， both groups showed declined 24 h-UTP， CHO， TG， and TCM symptom scores and elevated TP and ALB levels （P<0.01）， and the observation group had lower CHO， TG， and TCM symptom scores and higher TP and ALB than the control group （P<0.05）. ③ Safety indicators： After treatment， both groups showed declined white blood cell count （WBC）， red blood cell count （RBC）， hemoglobin （HB）， and alanine aminotransferase （ALT） （P<0.05， P<0.01） and elevated Glu （P<0.01） and blood urea nitrogen （BUN） （P<0.05）. After 24 weeks of treatment， none of WBC， RBC， HB， PLT， ALT， AST， BUN， Cr or Glu had significant differences between groups. Moreover， the incidence of adverse reactions showed no significant difference between the two groups. ConclusionThe TCM sequential syndrome differentiation protocol effectively reduces the relapse rate， improves the remission rate， shortens the time to proteinuria clearance， raised serum protein levels， lowers blood lipid levels， and alleviates symptoms， demonstrating good clinical safety in children with FRNS/SDNS.