Abstract Cross-linking of the dichotomous cell surface receptors for TNF-alpha (CD120a (p55) and CD120b (p75)) induces the activation of a variety of macrophage responses that mediate the role of this cell in inflammation and host defense. Although significant progress has been made in understanding the role that lipid second messengers play in mediating the action(s) of this multifunctional cytokine, less is known about the role of specific kinases in TNF-alpha-initiated signaling. We show that exposure of mouse macrophages to TNF-alpha stimulates a rapid and transient tyrosine phosphorylation and activation of p42mapk/erk2. By contrast, p44mapk/erk1 was found to be constitutively phosphorylated, with minimal further response to TNF-alpha. To investigate the use of CD120a (p55) and CD120b (p75) in the activation of p42mapk/erk2 in mouse macrophages, we determined the effects of blocking Ab on the activation of p42mapk/erk2 in response to TNF-alpha. In addition, we independently cross-linked each receptor with specific agonistic Ab, which have previously been shown to mimic the effects of TNF-alpha. Collectively, the results from these experiments indicate that cross-linking of CD120a (p55), but not that of CD120b (p75), was both necessary and sufficient for the activation of p42mapk/erk2 in mouse macrophages.