Epithelial membrane protein-2 (EMP2) is upregulated in a number of tumors and therefore remains a promising target for monoclonal antibody (mAb)-based therapy. In the current study, image guided therapy for an anti-EMP2 mAb was evaluated by positron emission tomography (PET) in both syngeneic and immunodeficient cancer models expressing different levels of EMP2 in order to enable a better understanding of its tumor uptake and off target accumulation and clearance. The therapeutic efficacy of the anti-EMP2 mAb was initially evaluated in high- and low-expressing tumors, and the mAb reduced tumor load for the high EMP2 expressing 4T1 and HEC-1-A tumors. To create an imaging agent, the anti-EMP2 mAb was conjugated to p-SCN-Bn-deferoxamine (DFO) and radiolabeled with 89Zr. Tumor targeting and tissue biodistribution were evaluated in syngeneic tumor models (4T1, CT26, and Panc02) and human tumor xenograft models (Ramos, HEC-1-A, and U87MG/EMP2). PET imaging revealed radioactive accumulation in EMP2 positive tumors within 24h post-injection, and the signal was retained for 5 days. High specific uptake was observed in tumors with high EMP2 expression (4T1, CT26, HEC-1-A, U87MG/EMP2), with less accumulation in tumors with low EMP2 expression (Panc02, Ramos). Biodistribution at 5 days post-injection revealed that the tumor uptake ranged from 2 to ~16 %ID/cc. The results show that anti-EMP2 mAbs exhibit EMP2-dependent tumor uptake with low off-target accumulation in preclinical cancer models. The development of improved anti-EMP2 antibody fragments may be useful to track EMP2 positive tumors for subsequent therapeutic interventions.