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In healthy individuals, immune control of persistent human cytomegalovirus (HCMV) infection is effectively mediated by virus-specific CD4+ and CD8+ T cells. However, identifying the repertoire of T cell specificities for HCMV is hampered by the immense protein coding capacity of this betaherpesvirus. Here, we present a novel approach that employs HCMV deletion mutant viruses lacking HLA class I immunoevasins and allows direct identification of naturally presented HCMV-derived HLA ligands by mass spectrometry. We identified 368 unique HCMV-derived HLA class I ligands representing an unexpectedly broad panel of 123 HCMV antigens. Functional characterization revealed memory T cell responses in seropositive individuals for a substantial proportion (28%) of these novel peptides. Multiple HCMV-directed specificities in the memory T cell pool of single individuals indicate that physiologic anti-HCMV T cell responses are directed against a broad range of antigens. Thus, the unbiased identification of naturally presented viral epitopes enabled a comprehensive and systematic assessment of the physiological repertoire of anti-HCMV T cell specificities in seropositive individuals., Competing Interests: Disclosures: M. Lübke reported a patent to HCMV epitopes (pending). S. Spalt reported a patent to HCMV epitopes (pending) and is currently an employee of Immatics Biotechnologies GmbH. D.J. Kowalewski reported a patent to HCMV epitopes (pending) and is currently an employee of Immatics Biotechnologies. C. Zimmermann reported a patent to HCMV epitopes (pending). L. Bauersfeld reported a patent to HCMV epitopes (pending). A. Nelde reported a patent to HCMV epitopes (pending). V.T.K. Le-Trilling reported a patent to HCMV epitopes (pending). H. Hengel reported a patent to HCMV epitopes (pending). H.-G. Rammensee reported "other" from Immatics GmbH and "other" from Curevac AG during the conduct of the study; in addition, H.-G. Rammensee had a patent to HCMV epitopes (pending). A. Halenius reported a patent to HCMV epitopes (pending). No other disclosures were reported., (© 2019 Lübke et al.)