Updated project metadata. In the last years the amount of ovine milk production, mainly used to formulate a wide range of different and exclusive dairy products often categorized as gourmet food, is progressively increasing. Taking also into account that sheep milk (SM) also appears to be potentially less allergenic than cow’s one, an in-depth information about its protein composition is essential to improve the comprehension of its potential benefits for human consumption and the role of milk components during cheese-making processes. The present work reports the results of an in-depth characterization of SM whey proteome, carried out by coupling the Combinatorial Peptide Ligand Library (CPLL) technology applied at three different pH values with SDS-PAGE and high resolution UPLC-nESI MS/MS analysis. This approach allowed the identification of 949 unique species that, to our knowledge, represent the largest description so far of the SM proteome. Particularly, this massive identification has expanded literature data about sheep whey proteome by 223 novel proteins previously undetected, many of which are involved in the defence/immunity mechanisms or in the nutrient delivery system. A comparative analysis of the proteins here identified with the inventory of the gene products discovered in cow’s milk whey to date, evidenced that about 50% of the identified components appear to be unique of sheep whey milk proteome and include a heterogeneous group of components which seem to have health-promoting benefits.