Nanoparticles are widely studied as theranostic vehicles for cancer; however, clinical translation has been limited due to poor tumor specificity. Features that maximize tumor uptake remain controversial, particularly when using clinically relevant models. We report a systematic study that assesses two major features for the impact on tumor specificity, i.e., active vs passive targeting and nanoparticle size, to evaluate relative influences in vivo. Active targeting via the V7 peptide is superior to passive targeting for uptake by pancreatic tumors, irrespective of nanoparticle size, observed through in vivo imaging. Size has a secondary effect on uptake for actively targeted nanoparticles in which 26 nm nanoparticles outperform larger 45 and 73 nm nanoparticles. Nanoparticle size had no significant effect on uptake for passively targeted nanoparticles. Results highlight the superiority of active targeting over nanoparticle size for tumor uptake. These findings suggest a framework for optimizing similar nonaggregate nanoparticles for theranostic treatment of recalcitrant cancers.