Background: ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) has demonstrated efficacy as a single agent for patients with neuroblastoma. Recent trials have focused on ¹³¹I-MIBG combination strategies, though little is known about the 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 ¹³¹I-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, 72 hours, 96 hours, and 15 days after ¹³¹I-MIBG infusion and determined levels of plasma FLT3 ligand, serum amylase, and gene expression for selected RNA transcripts (apoptosis, DNA damage response and cell cycle related). We evaluated marker association with treatment arm, clinical response using NANT response criteria, toxicity, and whole-body radiation dose. Results: The cohort included 99 patients who had at least one biomarker available for analysis (32 Arm A; 35 Arm B; 32 Arm C). We observed both positive and negative significant modulation in most biomarkers between baseline, 72 hours, and 96 hours following ¹³¹I-MIBG. Patients in Arm C had the lowest degree of modulation in FLT3 ligand. Elevated baseline levels of FLT3 ligand were significantly associated with improved Curie response but not overall response. Lower baseline BCL2 levels were associated with higher overall and Curie response. Patients with increased FLT3 ligand at 96 hours after ¹³¹I-MIBG therapy were significantly more likely to have grade 4 thrombocytopenia.Peripheral blood gene expression of the BCL2 family of apoptotic markers (BCL2/L1 and BAX) was significantly associated with grade 4 hematological toxicity. Whole-body radiation dose and PRKDC fold change at 72 hours were significantly correlated. No other individual biomarkers were correlated with whole body radiation dose at 72 or 96 hours post ¹³¹I-MIBG.Conclusions: Peripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation over time after ¹³¹I-MIBG treatment. Biomarkers related to hematopoietic damage and apoptosis were associated with hematological toxicity. Patients treated with vorinostat and ³¹I-MIBG had differential modulation of FLT3-ligand Further use of these biomarkers may improve our ability to care for patients treated with ¹³¹I-MIBG.