There are few data regarding adolescent-onset nephrotic syndrome (NS) and no guidelines for biopsy criteria and treatment protocol. This study was conducted to analyze the clinical spectrum of adolescent-onset NS and evaluate possible biopsy criteria in these children. A prospective analysis was carried out on all patients with idiopathic NS (fulfilling the ISKDC criteria) with onset between 1 and 18 years of age. They were evaluated clinically, followed by biochemical investigations and kidney biopsy. These characteristics of patients with onset between 1 and 12 years (group A) were compared with the same parameters in patients with onset between 12 and 18 years of age (group B) referred to our hospital over the same period. Among all clinical parameters, microhematuria was significantly more prevalent in adolescents (P<0.001). Kidney biopsy was performed in 88% of adolescent patients. Focal segmental glomerulosclerosis (FSGS) was the most-common histopathology in group B (46.3%) compared with minimal change disease (MCD) in group A (42.9%). Group B had a significantly higher frequency of membranoproliferative glomerulonephritis (MPGN) (P<0.005) and a significantly lower frequency of MCD (P<0.001). The biochemical parameters at the onset were similar. On comparing microhematuria, hypertension, and renal insufficiency at presentation, we observed that two or more of these features were present in all patients with MPGN and only in 19.6% of adolescents with MCD, mesangioproliferative glomerulonephritis, and FSGS. The frequency of steroid resistance was significantly higher in group B (P<0.001). In conclusion, adolescent-onset NS differs from the childhood variety in having a significantly higher frequency of hematuria, steroid resistance, and evidence of non-MCD, especially MPGN, on histopathology. Kidney biopsy can be restricted to those adolescents who have at least two abnormal clinical/biochemical features or are steroid non-responders.