The hot water extract of Salicornia herbacea, SHE, has recently been shown to have strong immunomodulatory activity. In the present study, we purified the polysaccharides, termed SHP, from SHE preparation and examined their immunomodulatory activity alone and in combination with interferon (IFN)-gamma. The combination of SHP and IFN-gamma synergistically inhibited the growth of the mouse monocytic cell line, RAW 264.7, inducing further differentiation to strongly adherent macrophages. The differentiation-inducing activity of SHP alone and in combination with IFN-gamma was confirmed by changes in the expression of differentiation antigens such as CD11b, CD18 and CD24. In addition, the combination of SHP and IFN-gamma synergistically activated RAW cells to produce cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta, and nitric oxide (NO). The synergistic activity of SHP was more prominent when SHP concentration was low. Increased production of TNF-alpha, IL-1 beta and NO was correlated with an increased level of their respective transcripts. These results confirm that Salicornia herbacea contains immunomodulatory polysaccharides that activate monocytes synergistically with small doses of IFN-gamma.