Background: We have previously found hyperreactive neutrophils, intrinsic or induced, in periodontitis patients by in vitro quantitation of free oxygen radicals. The effects of periodontitis and cigarette smoking on blood parameters have generally been described separately. Our aim was to compare these systemic effects of periodontitis and cigarette smoking, separately and in combination, in order to study the hyperreactivity in peripheral neutrophils. Methods: Blood cells and acute‐phase proteins were studied in 40 periodontitis patients and 43 healthy controls. The generation of free oxygen radicals from neutrophils was measured as luminolenhanced chemiluminescence (CL) after activation of their Fcγ receptors with opsonized Staphylococcus aureus. Results: An increase in CL in peripheral neutrophils from periodontitis patients was confirmed. Smoking had no significant effect on CL. The periodontitis patients had higher concentrations of C‐reactive protein (CRP) than the controls. ANOVA analysis showed that the increase in neutrophil count, haptoglobin, and α‐1 antitrypsin levels was significantly influenced by cigarette smoking. IgG2 was lower in patients than in controls (P <0.017, ANOVA), and there was an interaction between periodontitis and smoking (P <0.047, ANOVA). The lower concentration of IgG2 in patients who smoke may impair neutrophil function and be a mechanism by which smoking aggravates periodontitis. Conclusions: In general, the combination of periodontitis and cigarette smoking alters the parameters studied. The effects of periodontitis on CRP and IgG2 means that periodontal lesions may also leak agents, priming the peripheral neutrophils to increased CL. J Periodontol 1999;70:1355‐1360.