Soluble suppressor factor (SSF) is a recently purified human lymphokine produced by peripheral blood lymphocytes (PBL) in serum-free medium as a likely consequence of an autologous mixed lymphocyte reaction. Immunoregulatory actions of SSF include suppression of: polyclonal B cell activation, proliferative responses of normal PBL, and natural killer (NK) and antibody-dependent cellular cytotoxicity. We examined the ability of the monosaccharides fucose (Fuc), galactose (Gal), glucose (Glc), and mannose (Man) to reverse SSF-mediated suppression of NK activity. Fuc and Gal can partially or completely reverse SSF-mediated suppression at four effector:target cell ratios. Man and Glc were unable to significantly reverse SSF-mediated suppression. Fuc or Gal was added to PBL at various times after addition of SSF. SSF-mediated suppression of NK cytotoxicity becomes irreversible with respect to these monosaccharides during the first 24 hr of PBL exposure to SSF. To explore the mechanism behind this block of SSF-mediated suppression. Fuc or Gal (50 mM) was cultured with PBL for 24 hr before addition of SSF, or with SSF for 24 hr before addition to PBL. Our experiments indicate that SSF is directly interacting with these monosaccharides, and may function by recognizing specific sugar moieties on the surface of effector cells.