Earlier tumor detection can improve 5-year survival of patients, particularly among those presenting with cancers less than 1 cm in diameter. αvβ3-Targeted 111In nanoparticles (NP) were developed and studied for detection of tumor angiogenesis. Studies were conducted in New Zealand white rabbits implanted 12 days earlier with Vx-2 tumor. αvβ3-Targeted 111In/NP bearing ∼10 111In/NP vs. ∼1 111In/NP nuclide payloads were compared to nontargeted radiolabeled control particles. In vivo competitive binding studies were used to assess ligand-targeting specificity. αvβ3-Integrin-targeted NP with ∼10 111In/NP provided better (p < 0.05) tumor-to-muscle ratio contrast (6.3 ± 0.2) than ∼1 111In/NP (5.1 ± 0.1) or nontargeted particles with ∼10 111In/NP (3.7 ± 0.1) over the initial 2-hr postinjection. At 18 hr, mean tumor activity in rabbits receiving αvβ3-integrin-targeted NP was 4-fold higher than the nontargeted control. Specificity of the NP for the tumor neovasculature was supported by in vivo competition studies and by fluorescence microscopy of αvβ3-targeted fluorescent-labeled NP. Biodistribution studies revealed that the primary clearance organ in rabbits as a %ID/g tissue was the spleen. Circulatory half-life (t 1/2β) was estimated to be ∼5 hr using a 2-compartment model. αvβ3-Targeted 111In perfluorocarbon NP may provide a clinically useful tool for sensitively detecting angiogenesis in nascent tumors, particularly in combination with secondary high-resolution imaging modalities, such as MRI.