Although patients with refractory periodontitishave been widely reported, no clear biologic profile of these patients has been noted. The purpose of the present study was to evaluate host responsiveness of a well‐defined group of refractory periodontitis patients by determining the effect of a lipopolysaccharide (LPS) challenge on monocyte surface receptor density and on the release of inflammatory mediators. Venous blood was obtained from 7 refractory periodontitis, 8 stable periodontal maintenance, and 8 gingivitis patients with no evidence of periodontitis. Mononuclear cells were cultured in either control media or media treated withActinobacillus actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), orSalmonella typhimurium(S. typh) LPS. At 0 and 24 hours supernatants were assayed for prostaglandin‐E2(PGE2) and interleukin‐1β (Il‐1β) release by ELISA. Using flow cytometry the density of specific monocyte surface receptors were assayed with Mo3e and LeuM3 monoclonal antibodies (mAb); T‐cell CD4/CD8 ratios were assayed with OKT‐3, OKT‐4, and OKT‐8 mAb. After 24 hours incubation withPgorS. typhLPS, the upregulation of the Mo3e receptor was significantly decreased for refractory periodontitis patients (P<0.05) when compared to gingivitis and to stable maintenance patients. In refractory periodontitis patients the T‐cell CD4/CD8 ratio was decreased. Upon stimulation withPgorS. typhLPS, monocytes from stable maintenance and refractory periodontitis patients released more Il‐1β (P<0.05) and PGE2(P= 0.13 and 0.15) than monocytes from gingivitis subjects. The current data suggest that, as assessed by the inflammatory mediator release of Il‐1β and PGE2, monocytes from both stable maintenance and refractory periodontitis patients may have the potential for a more vigorous inflammatory response to a given bacterial challenge, when compared to monocytes from individuals without a previous history of periodontitis. However, only refractory periodontitis patients had a decreased CD4/CD8 ratio and decreased Mo3e expression, representing some alteration in the mononuclear cell‐cytokine system, that distinguished them from patients who responded predictably to treatment.J Periodontol 1994;65:8–16.