A single-dose study was conducted to characterize the safety, pharmacokinetic, immunogenicity, and pharmacodynamic activity of highly purified Staphylococcal protein A (SPA), a native bacterial protein with immune-modulatory activity. Twenty healthy adults received a single intravenous dose of either 0.3 μg/kg (n = 8) or 0.45 μg/kg (n = 8) of SPA or placebo (n = 4). Changes in C-reactive protein and neopterin were used as markers of immune activation. All treatment-related AEs were of mild severity. Twelve of 16 active-dosed subjects developed detectable anti-protein A antibodies after dosing. These subjects had notably more rapid plasma clearance of SPA even prior to development of detectable titers. A transient post-dose decrease in circulating lymphocytes was observed as a notable pharmacodynamic effect, but was not correlated with plasma clearance or AUC. In peripheral blood mononuclear cells, SPA dosing increased transcription of multiple genes regulated by type-1 interferons, and up-regulation of several of these genes correlated with the degree of lymphopenia seen 24 hours after dosing. This study demonstrates the safety and tolerability of small intravenous doses of SPA and delineates acute and transient pharmacodynamic effects not previously reported.