This dataset presents the results of protein sample preparation strategies for enriching a novel encyclopaedic peptide spectral library using the liquid fraction of sheep blood. The method used showed the capability of simultaneously detecting hundreds of key proteins in the liquid fraction of blood (circulating acellular proteome) using sheep as a model by: a) Prototyping of the circulating acellular proteome of healthy sheep using serum b) A comprehensive analysis of fractions of acetone precipitated sheep serum and plasma; c) A comprehensive analysis of fractions of partial organic precipitation of sheep serum and plasma proteins using acetonitrile; d) Combinatorial peptide ligand library protein enrichment of sheep serum and plasma; e) Off-gel fractionation of serum proteins; f) Extraction of protein data from ex-diagnostic sheep serum; g) Derivation of peptide data from serum and plasma of endotoxin treated sheep.