Ginseng (GS) has been used as an herbal medicine for centuries and it has become widely used all over the world based on claims that regular use of GS extracts has multiple beneficial biological effects including prevention of diseases and enhancing immunity. However, the mechanism of immunomodulatory effects remain unclear because most of the studies to date have used neoplastic cell lines whose results may not be extrapolated to normal human immune cells. Therefore, the goal of this study was to characterize the effects of standardized North-American ginseng (Panax quinquefolius) extracts (ethanol, aqueous and crude polysaccharide extracts) on the innate and adaptive immune responses of human peripheral blood mononuclear cells (PBMCs) of healthy volunteers. Our results showed that endotoxin (LPS)-free GS by itself induced the production of pro-inflammatory cytokines (IL-1β, IL-6, TNFα) and of IL-10 by PBMCs. Of the three different GS extracts tested the aqueous extract was the most potent. The pro-inflammatory response induced by LPS was rather enhanced by GS extracts. However, the adaptive T cell IL-2 response to bacterial superantigens was down-regulated in the presence of GS. The immunomodulatory effects of GS were associated with activation of the MAPK (ERK1/2), the PI3K/Akt, and the NF-κB signalling pathways and could be inhibited by pharmacological blockade of these pathways. Initial fractionation by size-exclusion column chromatography of GS extracts suggests that the immunomodulatory effects may be mediated by high molecular weight compounds within the GS extracts. Based on these results, we conclude that GS, and in particular its aqueous extract containing high molecular weight compounds, has modulatory properties on innate and adaptive immune responses through a complex profile of pro-inflammatory and anti-inflammatory cytokine production and signalling cascades. This work should help to focus the search for specific active compounds in these extracts with immunomodulatory capacity.