Herein we studied the accumulation and decay of CD2 mRNA in human PBMC stimulated with PHA. The data show that CD2-specific messages are present in low quantities in resting PBMC and are rapidly increased by five- to sevenfold within 24 h of addition of optimal amounts of PHA. Similar induction of CD2 mRNA was seen after stimulation of PBMC with anti-CD3 mAb and PMA. Peak levels of CD2 message were maintained until 72 h post-stimulation and declined gradually thereafter. Despite stimulation with Staphylococcus aureus and PMA, purified B cells failed to demonstrate any CD2 mRNA. Unlike transferrin or IL-2R mRNA, Il-2 had no effect on the accumulation of CD2 messages in resting or PHA-stimulated PBMC. The time course of CD2 mRNA accumulation preceded lymphocyte proliferation and the appearance of additional cell surface CD2 Ag. The decay of CD2 mRNA was very rapid, with a t 1/2 of approximately 45 min. The protein synthesis inhibitor, cycloheximide, increased its half-time by fourfold to 3.5 h. The data imply the existence of a labile factor, dependent on protein synthesis that is important in the regulation of CD2 mRNA. Compared to other PHA-inducible lymphocyte genes, the kinetics of CD2 transcript accumulation are most reminiscent of the oncogenes N-ras and c-abl.