Background: This study was performed in order to determine whether monocyte in vitro function is associated with presence, stage and prognosis of head and neck squamous cell carcinoma ( HNSCC) disease. Methods: Prospective study describing outcome, after at least five years observation, of patients treated for HNSCC disease in relation to their monocyte function. Sixty-five patients with newly diagnosed HNSCC and eighteen control patients were studied. Monocyte responsiveness was assessed by measuring levels of monocyte in vitro interleukin ( IL)- 6 and monocyte chemotactic peptide ( MCP)-1 secretion after 24 hours of endotoxin stimulation in cultures supplied either with 20% autologous serum ( AS) or serum free medium ( SFM). Survival, and if relevant, cause of death, was determined at least 5 years following primary diagnosis. Results: All patients, as a group, had higher in vitro monocyte responsiveness in terms of IL- 6 ( AS) ( t = 2.03; p < 0.05) and MCP-1 ( SFM) ( t = 2.49; p < 0.05) compared to controls. Increased in vitro monocyte IL- 6 endotoxin responsiveness under the SFM condition was associated with decreased survival rate ( Hazard ratio ( HR) = 2.27; Confidence interval ( Cl) = 1.05 - 4.88; p < 0.05). The predictive value of monocyte responsiveness, as measured by IL- 6, was also retained when adjusted for age, gender and disease stage of patients ( HR = 2.67; Cl = 1.03 - 6.92; p < 0.05). With respect to MCP- 1, low endotoxin- stimulated responsiveness ( AS), analysed by Kaplan- Meier method, predicted decreased survival (. = 4.0; p < 0.05). Conclusion: In HNSCC patients, changed monocyte in vitro response to endotoxin, as measured by increased IL- 6 ( SFM) and decreased MCP- 1 ( AS) responsiveness, are negative prognostic factors.