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Purpose: The study was undertaken to develop and evaluate the potential of an integrin α v β 6 -binding peptide (α v β 6 -BP) for noninvasive imaging of a diverse range of malignancies with PET., Experimental Design: The peptide α v β 6 -BP was prepared on solid phase and radiolabeled with 4-[ 18 F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using paired α v β 6 -expressing and α v β 6 -null cell lines. In vivo evaluation (PET/CT, biodistribution, and autoradiography) was performed in a mouse model bearing the same paired α v β 6 -expressing and α v β 6 -null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast, or pancreatic cancer., Results: [ 18 F]α v β 6 -BP displayed excellent affinity and selectivity for the integrin α v β 6 in vitro [IC 50 (α v β 6 ) = 1.2 nmol/L vs IC 50 (α v β 3 ) >10 μmol/L] in addition to rapid target-specific cell binding and internalization (72.5% ± 0.9% binding and 52.5% ± 1.8%, respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [ 18 F]α v β 6 -BP was rapid, primarily via the kidneys. In patients, [ 18 F]α v β 6 -BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [ 18 F]α v β 6 -BP in both the primary lesion and metastases, including metastasis to brain, bone, liver, and lung., Conclusions: The clinical impact of [ 18 F]α v β 6 -BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies., (©2018 American Association for Cancer Research.)