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Cancer is the leading cause of death in dogs, yet there are no established screening paradigms for early detection. Liquid biopsy methods that interrogate cancer-derived genomic alterations in cell-free DNA in blood are being adopted for multi-cancer early detection in human medicine and are now available for veterinary use. The CANcer Detection in Dogs (CANDiD) study is an international, multi-center clinical study designed to validate the performance of a novel multi-cancer early detection "liquid biopsy" test developed for noninvasive detection and characterization of cancer in dogs using next-generation sequencing (NGS) of blood-derived DNA; study results are reported here. In total, 1,358 cancer-diagnosed and presumably cancer-free dogs were enrolled in the study, representing the range of breeds, weights, ages, and cancer types seen in routine clinical practice; 1,100 subjects met inclusion criteria for analysis and were used in the validation of the test. Overall, the liquid biopsy test demonstrated a 54.7% (95% CI: 49.3-60.0%) sensitivity and a 98.5% (95% CI: 97.0-99.3%) specificity. For three of the most aggressive canine cancers (lymphoma, hemangiosarcoma, osteosarcoma), the detection rate was 85.4% (95% CI: 78.4-90.9%); and for eight of the most common canine cancers (lymphoma, hemangiosarcoma, osteosarcoma, soft tissue sarcoma, mast cell tumor, mammary gland carcinoma, anal sac adenocarcinoma, malignant melanoma), the detection rate was 61.9% (95% CI: 55.3-68.1%). The test detected cancer signal in patients representing 30 distinct cancer types and provided a Cancer Signal Origin prediction for a subset of patients with hematological malignancies. Furthermore, the test accurately detected cancer signal in four presumably cancer-free subjects before the onset of clinical signs, further supporting the utility of liquid biopsy as an early detection test. Taken together, these findings demonstrate that NGS-based liquid biopsy can offer a novel option for noninvasive multi-cancer detection in dogs., Competing Interests: AF, KMK, JAT, LMM, JMR, PCF, GEH, FM, PN, CAR-P, DMF, TJ, RM-P, KW, ALM-W, DSG, AP, KM, SCH, KML, LH, JC, IC, and DWYT are employed by or affiliated with PetDx; and receive compensation from PetDx and/or hold vested or unvested equity in PetDx. Drs. Flesner and Leibman are members of the PetDx clinical advisory board and receive compensation and equity. Dr. Borgatti has ownership interest (including patents) in a patent entitled “Reduction of EGFR therapeutic toxicity” filed by the University of Minnesota Office of Technology Commercialization. Drs. Cahalane, Phillips, and Aiken are investors in PetDx. Drs. Jensen, van den Boom, Dharajiya, and Diaz are advisors for PetDx and hold vested or unvested equity in PetDx. Drs. Chorny, Kruglyak, Grosu, Marass, Ruiz-Perez and Tsui hold pending patent applications related to technology described in this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.