The purpose of this investigation was to further characterize the marked increase in intracellular cAMP which follows the interaction of human lymphocytes and latex polymers. Six distinct cell types, each of which either bind or ingest these latex particles, were studied; however, only lymphocytes responded with increases in intracellular cAMP. The initial attachment of the latex particles to the lymphocyte surface was independent of temperature, cyclic nucleotides and divalent cations in the external milieu. The subsequent cAMP response was maximal at physiologic temperatures and modulated by agents thought to alter microfilament and microtubule function. Four different types of polymers produced increases in intralymphocytic cAMP and the maximal increases were confined to particles having a mean diameter of 0.4-2.02 μm. Within this latter size range, there was a close correlation between the number of membrane-associated particles and the magnitude of the cAMP response. Similarities to the lymphocyte-lectin activation system included: 1. 1. A requirement for binding of the latex polymers to the external plasma membrane. 2. 2. A biphasic cAMP response characterized by an early rise followed by a later fall. 3. 3. Modulation of this response by pharmacologic agents which compromise microtubule and microfilament function. In contrast to the lectin-induced activation, latex beads inhibited amino acid transport and phosphatidylinositol turnover and did not lead to later increases in DNA synthesis. These data suggest that latex polymers attach to receptors on the plasma membrane different from those responsible for lymphocyte activation, and through cAMP induce metabolic responses dissimilar to those associated with lectin activation.