Syntaxin-11 is a member of a family of membrane-trafficking proteins referred to as soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Recent studies have shown that syntaxin-11 is expressed in natural killer cells and cytotoxic T cells and is likely to play a role in the granule exocytosis pathway. However, the biological role of syntaxin-11 in other immune cells has remained elusive. This study found that stimulation with interferon-gamma upregulated syntaxin-11 expression in primary monocytes. Experiments using monocytes from patients with familial haemophagocytic lymphohistiocytosis harbouring mutations in the gene encoding syntaxin-11 (STX11), or monocytes from healthy individuals in which syntaxin-11 was downregulated using specific short-interfering RNA, demonstrated that syntaxin-11 was not required for antibody-dependent cellular cytotoxicity. On the other hand, silencing of syntaxin-11 expression in primary macrophages enhanced the phagocytosis of apoptotic target cells with a concomitant increase in macrophage secretion of tumour necrosis factor-alpha. Moreover, Fcgamma-receptor-mediated uptake of target cells was also enhanced following silencing of syntaxin-11 expression in macrophages. In addition, syntaxin-11 localized to the plasma membrane in macrophages ingesting apoptotic cell corpses. Syntaxin-11 thus appears to act as a negative regulator of human macrophage engulfment of apoptotic cells and IgG-opsonized red blood cells.