Neuroblastoma is the most common malignancy in infants. Overexpression of the epidermal growth factor receptor (EGFR) in neuroblastoma tumors underlies resistance to chemotherapeutics. UBE4B, an E3/E4 ubiquitin ligase involved in EGFR degradation, is located on chromosome 1p36, a region in which loss of heterozygosity is observed in approximately one-third of neuroblastoma tumors and is correlated with poor prognosis. In chemoresistant neuroblastoma cells, depletion of UBE4B yielded significantly reduced cell proliferation and migration, and enhanced apoptosis in response to EGFR inhibitor, Cetuximab. We have previously shown that UBE4B levels are inversely correlated with EGFR levels in neuroblastoma tumors. We searched for additional targets of UBE4B that mediate cellular alterations associated with tumorogenesis in chemoresistant neuroblastoma cells depleted of UBE4B using reverse phase protein arrays. The expression of STAT5a, an effector protein downstream of EGFR, doubled in the absence of UBE4B, and verified by quantitative immunoblotting. Chemoresistant neuroblastoma cells were treated with SH-4-54, a STAT5 inhibitor, and observed insignificant effects on cell proliferation, migration, and apoptosis. However, SH-4-54 significantly enhanced the anti-proliferative and anti-migratory effects of Cetuximab in naïve SK-N-AS neuroblastoma cells. Interestingly, in UBE4B depleted SK-N-AS cells, SH-4-54 significantly potentiated the effect of Cetuximab rendering cells increasingly sensitive an otherwise minimally effective Cetuximab concentration. Thus, neuroblastoma cells with low UBE4B levels were significantly more sensitive to combined EGFR and STAT5 inhibition than parental cells. These findings may have potential therapeutic implications for patients with 1p36 chromosome LOH and low tumor UBE4B expression.