Although chloroquine administration in vivo following haemorrhage in mice decreases tumour necrosis factor-α (TNF-α) release by macrophage (M∅), the mechanism remains unknown. To study this, peritoneal M∅ (pM∅) from unmanipulated, sham-operated and post-haemorrhage mice were isolated, treated with 0.13 mg/ml chloroquine for 2 hr, and then stimulated with lipopolysaccharide (LPS) for 48 hr. Pretreatment of pM∅ from various groups of mice with chloroquine resulted in 75-90% inhibition of TNF-α release, determined by bioassay. Total RNA was isolated from pM∅ and murine M∅-derived cell lines (P388D1 and RAW 264.7), stimulated with LPS for 0.5 or 1 hr, respectively, and Northern blot analysis for TNF-α mRNA performed. Chloroquine inhibited TNF-α mRNA expression without interfering with mRNA stability, suggesting that this agent reduces M∅ TNF-α release by disrupting TNF-α gene transcription.