The presence of growth hormone (GH) receptor (GHR) gene transcripts and GH-binding sites in guinea pig liver suggests normal expression and translation of a GHR gene in these animals. Guinea pigs are, however, resistant to GH action and appear to lack the circulating GH-binding proteins (GHBPs) that result from alternate splicing of the GHR message or from cleavage of the extracellular binding domain of membrane GHRs. The paradoxical absence of circulating GHBPs in guinea pigs was therefore examined. The presence of GHR/GHBP mRNA in guinea pig liver was confirmed by Northern blotting. In addition to a 4.4 kb transcript that probably encodes a full-length receptor, an additional 1.9 kb transcript was detected that may encode a binding protein, although this transcript is larger than rat GHBP mRNA. The possibility that these transcripts may be translated into GHBPs was assessed immunologically. A 46 kDa protein, identical in size to rat GHBP, was specifically detected in guinea pig liver by a monoclonal antibody (MAb 4.3) raised against the hydrophilic tail of rat GHBP. A single protein of approximately 48 kDa was also detected by MAb 4.3 in proteins precipitated from guinea pig serum by a polyclonal antibody raised against the rat GHBP. This protein was slightly larger than the two proteins (46 kDa and 40 kDa) in rat serum labelled by the same method. The presence of a putative GHBP in guinea pig serum was also supported by the cross-reactivity of guinea pig serum with a monoclonal antibody (MAb 263) raised against rat GHBP. The binding of radioiodinated hGHBP to this antibody was inhibited, in a dose-related way and parallel to that of the standard, by serial dilutions of guinea pig serum, indicating immunoreactive GHBP concentrations > 500 ng/ml. Immunoreactive GHBP concentrations in other mammalian serum (from rats, rabbits, pigs, cattle, horses, goats, dogs and humans) were, in contrast, < 30 ng/ml. Guinea pig sera similarly cross-reacted, but to a lesser degree, in other radioimmunoassays for rGHBP, in which p(Ab)1 or MAb 4.3 were used as the primary antibodies. Nevertheless, despite these immunological findings, hGH binding activity could not be detected in guinea pig serum using a number of different radioligand binding assays. These results suggest the novel presence of abundant, but possibly defective, GHBP-like proteins in guinea pig serum. The immunological detection of the hydrophilic sequence of rat GHBP in guinea pig hepatic and serum proteins also suggests that GHBPs in this species arise from the truncated GHR gene transcript identified in guinea pig liver.