Full-thickness 5 mm punch biopsy wounds were made lateral to the sacrum in 48 smokers and 30 never smokers. After 1 week, the wounds were excised and fixed. The smokers were then randomized to continuous smoking or abstinence with a transdermal nicotine patch or a placebo patch. The sequence of wounding and excision was repeated after 4, 8, and 12 weeks. All excised tissue was stained with hematoxylin-eosin and immunohistochemically for macrophages (CD68), procollagen 1 N-terminal propeptide (PINP) in fibroblasts, and endothelial cells (CD31). The cellularity was assessed and scored by two independent histopathologists, and for the analysis, proportional odds models and random effect models for repeated measurements were applied. Macrophages and PINP-stained fibroblasts were reduced in the smokers' wounds (0.28 [0.14-0.58] [OR, 95%CI]; p=0.01 and 0.37[0.19-0.70]; p<0.01, respectively, when compared with never smokers' wounds). Inflammation scores were marginally affected. Following smoking cessation, inflammatory cell infiltration and macrophages in the wounds increased. PINP-stained fibroblasts were unaffected. Neovascularization was not affected by smoking or abstinence. Wound inflammation and fibroblast proliferation were attenuated in smokers, suggesting delayed healing. Abstinence from smoking restores inflammation, but does not affect proliferation. These findings suggest a pathophysiologic mechanism for postoperative wound infection and dehiscence in smokers and why smoking cessation appears to reduce wound infection but not dehiscence.