BACKGROUND After major trauma and sepsis, patients frequently show a decreased blood glutamine (Gln) level. Gln deprivation has been shown to induce apoptosis in intestinal epithelial cells. In this study, we investigated whether the Gln level also affects the susceptibility of monocytic cells to apoptosis. METHODS Human monocytic U937 cells were suspended in a Gln-free medium, exposed for 20 minutes to either tumor necrosis factor alpha, Fas ligand, heat shock, or UV irradiation and allowed to recover for 4 hours or 24 hours. Apoptosis was measured by annexin-V assay and confirmed by nuclear condensation. The activation of caspase-3 was determined by Western blot. RESULTS When induced by tumor necrosis factor alpha, Fas ligand, or heat shock, the apoptosis rate was significantly lower (50%-60%) in the presence of Gln than in the absence of Gln (P <.02). However, Gln had no effect on UV irradiation-induced apoptosis. Caspase-3 was activated by all inducers and was independent of Gln. CONCLUSIONS This study shows that glutamine deprivation increases the susceptibility of monocytic cells to some but not all inducers of apoptosis. Because Gln has no effect on caspase-3 activation, we hypothesize that the selective anti-apoptotic effect of Gln occurs downstream of caspase-3. These results suggest that Gln serves as a selective immunomodulating factor.