Integrin α6 emerges to be a diagnostic biomarker for hepatocellular carcinoma (HCC). Here, we translated our previously identified integrin α6 targeted peptide RWY into a positron emission tomography (PET) tracer ¹⁸F-RWY for the detection of HCC lesions in following four HCC mouse models including subcutaneous, orthotopic, genetically engineered and chemical induced HCC mice. ¹⁸F-RWY produced high PET signals in liver tumor tissues that were reduced by blocking studies using nonradiolabeled RWY peptide. We compared the integrin α6 targeted PET tracer ¹⁸F-RWY with the integrin αvβ3-targeted PET tracer ¹⁸F-3PRGD₂ and the clinical PET tracer ¹⁸F-FDG in chemical induced HCC mice. Among 12 HCC identified by enhanced magnetic resonance imaging (MRI) with hepatocellular specific gadoxetate disodium Gd-EOB-DTPA, the sensitivities of ¹⁸F-RWY, ¹⁸F-3PRGD₂ and ¹⁸F-FDG were approximately 92%, 73% and 50% while the tumor-to-liver ratios were 4.36 ± 1.41, 1.97 ± 0.43 and 1.63 ± 0.23 respectively. Additionally, PET imaging with the integrin α6 targeted ¹⁸F-RWY enabled to visualize small HCC lesions with diameters approximately 0.2 cm that was hard to be distinguished from surround hepatic vascular by enhanced MRI with Gd-EOB-DTPA. These findings potentiate the use of integrin α6 targeted PET tracer ¹⁸F-RWY for the detection of HCC.