Inflamed gingival tissues are enriched in macrophages (MOs) and CD4-positive T cells; however, T helper-type cytokines such as interleukin (IL)-2 and IL-4 are absent. Therefore, we investigated whether a relationship exists between IL-4 receptor (IL-4R) expression and MO persistence in the absence of exogenous IL-4. Gingival MOs, when compared with monocyte(MN)/MOs from peripheral blood mononuclear cells, expressed high levels of IL-4R mRNA. Furthermore, in vitro cultures of gingival MOs remained viable whereas identically treated peripheral blood MN/MOs rapidly lost viability. However, when gingival MOs were incubated with recombinant IL-4 (rIL-4), the cell viability was dramatically reduced. When the frequency of apoptotic cells was assessed in rIL-4-treated gingival MO cultures, higher numbers of apoptotic cells were noted in rIL-4-treated versus control cultures. Furthermore, rIL-4-treated MOs from inflamed gingiva showed DNA fragmentation as assessed by electrophoresis. These findings clearly show that addition of exogenous rIL-4 to gingival MO cultures leads to cell death by apoptosis. This finding would suggest that topical application of rIL-4 may inhibit the persistence of MOs in adult periodontitis, which could then lead to decreased inflammation.