Background: ¹³¹I-metaiodobenzylguanidine (MIBG), a radiopharmaceutical agent, has demonstrated efficacy as a single agent for patients with neuroblastoma. Recently, trials have focused on MIBG combination strategies, though little is known about impact of combination agents on markers of radiation exposure. Methods: NANT11-01 (NCT02035137) was a multicenter, open label, randomized phase II clinical trial that evaluated MIBG therapy alone (Arm A) or in combination with vincristine/irinotecan (Arm B) or vorinostat (Arm C) for patients with resistant/relapsed neuroblastoma. We collected blood samples at baseline and 72 hours after MIBG infusion and determined plasma flt3 ligand, serum amylase, gamma-H2AX levels, and gene expression for key transcripts. We plotted relative change from baseline and evaluated association of marker modulation by treatment arm and clinical response using NANT response criteria. Results: The cohort included 65 patients who had at least one biomarker available for analysis (19 Arm A; 24 Arm B; 22 Arm C). Across all arms, plasma flt3 ligand and serum amylase were significantly positively modulated while BCLXL/BCL2L1 and BCL2 gene expression demonstrated significant negative modulation by 72 hours after MIBG infusion compared to baseline (p < 0.001 for all markers). For patients randomized to Arm B, we observed significantly greater positive modulation of Flt3 ligand (geometric mean fold change 4.21 for Arm B vs. 2.22 and 2.08 for Arms A and C, respectively; p < 0.001) and significantly greater negative modulation of BCLXL/BCL2L1 (geometric mean fold change 0.11 for Arm B vs. 0.55 and 0.43 for Arms A and C, respectively; p < 0.001). There were no statistically significant associations of differential modulation of a specific biomarker with higher likelihood of response (partial response or better), though there was a trend to suggest that responders had greater gamma-H2AX modulation (p = 0.053).Conclusions: Peripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation after MIBG treatment, with differential modulation when chemotherapy is combined with MIBG. Analysis of additional markers and additional samples is ongoing. Clinical trial information: NCT02035137