Methyl inosine monophosphate (MIMP) augments preferentially the in vitro responses of human and murine lymphocytes to a T-cell mitogen such as phytohemagglutinin (PHA) and inconsistently to a B-cell mitogen such as pokeweed or lipopolysaccharide (LPS). In a normal interleukin-2-dependent cell line (CTLL), MIMP showed little or no effect on IL-2 action; however, in a murine CTLL line exhibiting impaired responses to IL-2, MIMP stimulated thymidine incorporation and restored the response to IL-2. MIMP augments the PHA responses of both CD4+ and CD8+ human peripheral blood T-cells. The effect of MIMP to augment the PHA response of human lymphocytes is paralleled by the parent molecule, IMP. MIMP, but not IMP, is resistant to hydrolysis by 5'nucleotidase; thus, MIMP appears to be a protected analogue of IMP which is capable of in vivo action. MIMP (100 micrograms/ml) augments the PHA responses of 15 to 24 elderly humans. MIMP also augments the PHA responses of eight HIV-infected pre-AIDS patients but not of eight AIDS patients. When PHA responses of human lymphocytes are suppressed in vitro by an HIV-derived immunosuppressive peptide, interferon alpha, or prostaglandin PGE2, MIMP (0.1-100 micrograms/ml) progressively restores the depressed response; however, when the suppression is severe (greater than 50%), MIMP cannot restore the response. These data indicate that MIMP potentiates normal T-lymphocyte mitogen responses and restores those impaired by a variety of inflammatory and immunosuppressive influences.