BACKGROUND: The Patient Reported Outcomes Measurement Information System (PROMIS) II is a prospective study that evaluates patient reported outcomes in pediatric chronic diseases as a measure of health-related quality of life (HRQOL). We have evaluated the influence of disease duration on HRQOL and, for the first time, compared the findings of the PROMIS measures to those of the PedsQL™ 4.0 Generic Scales (PedsQL) from the PROMIS II nephrotic syndrome (NS) longitudinal cohort. METHODS: This was a prospective study in which 127 children (age range 8-17 years) with active NS from 14 centers were enrolled. Children with active NS defined as the presence of nephrotic range proteinuria (>2+ urinalysis and edema or urine protein/creatinine ratio >2 g/g) were eligible. Comparisons were made between children with prevalent (N = 67) and incident (N = 60) disease at the study enrollment visit. RESULTS: The PROMIS scores were worse in prevalent patients in the domains of peer relationship (p = 0.01) and pain interference (p < 0.01). The PedsQL showed worse scores in prevalent patients for social functioning (p < 0.01) and school functioning (p = 0.03). Multivariable analyses showed that prevalent patients had worse scores in PROMIS pain interference (p = 0.02) and PedsQL social functioning (p < 0.01). CONCLUSION: The PROMIS measures detected a significant impact of disease duration on HRQOL in children, such that peer relationships were worse and pain interfered with daily life to a greater degree among those with longer disease duration. These findings were in agreement with those for similar domains in the PedsQL legacy instrument.