Background: Human anti-mouse antibody (HAMA) response after mouse anti-GD2 antibody therapy was demonstrated to correlate with overall survival (OS) in patients with neuroblastoma [Cheung et al. JCO 33:755, 2015]. Association of OS with idiotype network (anti-GD2 antibody(Ab3’) or anti-anti-idiotypic antibody (Ab3) was proposed [Cheung et al. Clin Cancer Res 6:2653, 2000]. We test this hypothesis in a large cohort of patients with long term follow up. Methods: 395 children with high risk stage 4 ( > 18 months or MYCN amplification) neuroblastoma received anti-GD2 antibody 3F8 therapy between 1991 and 2010. By 18 months most patients have completed all 3F8 cycles. Upon receiving high dose chemotherapy, their B cell function would have returned to normal range [Small et al. Blood 76:1847, 1990]. Anti-GD2 antibody titers (Ab3’) in sera before 3F8 treatment and at 18 months (± 30 days) after starting 3F8 were analyzed. OS and progression free survival (PFS) from date of sampling were estimated using Kaplan-Meier method. The impact of Ab3’ on survival was examined using log-rank test. Results: Among these patients, the ability to mount HAMA response at any time before relapse was associated with improved survival from first 3F8 treatment. Available serum samples from all patients alive at 18 months from the beginning of 3F8 were studied, including those treated with 3F8 in first remission (n = 72), second remission (n = 16), and those with primary refractory disease (n = 41). Fifty-three patients (41%) had positive Ab3’ response associated with significantly better OS (5-year survival: 83% vs 66%, P < 0.05) with median follow up of 64 months (3-236 months). Similar trend was found in PFS but statistically insignificant (5-year PFS: 68% vs 57%, P = 0.31). Univariate analysis showed that pretreatment variables (gender, age at diagnosis, MYCN amplification, and autologous stem cell transplant) were not predictive of OS. Conclusions: Long term followup demonstrated that idiotype network after 3F8 treatment was associated with improved OS in patients with high risk stage 4 neuroblastoma.