This study examined immune/inflammatory parameters following an acute tobacco smoking episode in smokers with varying smoking histories. Twenty-eight male habitual smokers were categorized according to smoking history, e.g. younger smoker (YSM) or middle-aged smoker (MSM). Participants were matched for fitness and smoking habits and following baseline testing, undertook a smoking protocol involving consumption of two cigarettes within 15 min. Venous blood was collected pre- and immediately, 1 h, and 4 h post-protocol to permit analyses of circulating levels of interleukin (IL)-6, IL-1β, IL-1ra, monocyte chemoattractant protein-1 (MCP-1), C-reactive protein (CRP), and leukocytes. No baseline differences were observed between groups for IL-1ra, IL-1β, or leukocytes. MCP-1 and IL-6 levels were significantly (p < 0.05) elevated at baseline in YSM. Both groups showed an increase in MCP-1 levels from pre- to immediately post-cigarette consumption. The MSM also displayed an increase in IL-6 post-smoking, followed by a decline over the period from 1 to 4 h thereafter. A significant decline in circulating lymphocyte and eosinophil levels from immediately post-cigarette consumption to 1 h later was observed in both groups. Monocyte levels in the YSM followed a similar profile but no significant effects on this cell type were evident in the MSM. From these results, a 10-year difference in smoking history induces mild leukopenia. Altered responses due to smoking were also evident with respect to levels of circulating biomarkers, which may be indicative of an effect of differences in cumulative smoking history.