We investigated tumor-free mucosa and squamous cell carcinomas of the oral cavity, the pharynx, and larynx with respect to the presence of stromal CD34+ fibrocytes and alpha-smooth muscle antigen (SMA)-positive myofibroblasts. Additionally, stromal expression of CD117 was analyzed. A total of 39 squamous cell carcinomas were assessed immunohistochemically. In all cases investigated, CD34+ fibrocytes were found in the tumor-free stroma, whereas alpha-SMA-positive myofibroblasts were lacking. Areas of lymphocytic infiltration disclosed a focal reduction of CD34+ fibrocytes. CD117 expression was absent from the tumor-free stroma. Of 39 squamous cell carcinomas, 33 were free of stromal CD34+ fibrocytes, and, in 31 carcinomas, stromal alpha-SMA-positive myofibroblasts occurred at least focally. CD117-positive stromal spindle cells were found in 25 carcinomas. Compared with tumor-free mucosa, the number of tissue mast cells was significantly increased in carcinomas. We conclude that stromal remodeling induced by invasive carcinomas is characterized by a loss of CD34+ fibrocytes and subsequent gain of alpha-SMA-positive myofibroblasts. The diagnostic impact of this finding is, however, limited by the fact that chronic inflammation may also be accompanied by a focal loss of CD34+ fibrocytes.