Alcohol abuse has long been known to adversely affect innate immune responses and predispose to infections. One cellular mechanism responsible for this effect is alcohol-induced suppression of TNF-alpha by mononuclear phagocytes. We undertook experiments to better understand the cellular mechanisms by which alcohol dose-dependently suppresses TNF elaboration by human monocytes. Here we show in human primary monocytes and cell lines that alcohol suppresses LPS-induced TNF secretion post-transcriptionally by inhibiting cellular processing by TNF-alpha-converting enzyme (TACE). Using fluorescent resonance energy transfer microscopy, physiological relevant levels of alcohol resulted in a reversible dose-dependent decrease in fluorescent resonance energy transfer efficiency between TNF and TACE. These data demonstrate that alcohol inhibits interactions between TNF and its converting enzyme, TACE, possibly by affecting membrane fluidity. These data in part explain the cellular mechanisms by which alcohol impairs monocyte function and may identify immunotherapeutic targets aimed at restoring immune function in this at-risk patient population.