Differential diagnosis between keratoacanthomas and well differentiated squamous cell carcinomas based on clinical and histomorphological data is problematic. Recent findings of cellular atypia in a large proportion of keratoacanthomas indicated that these potentially 'self-healing' cutaneous neoplasms had the potential for malignant progression. Another malignancy-associated criterion is enhanced angiogenesis with increased microvessel density. To provide further diagnostic markers for keratoacanthomas we examined microvessel density on paraffin sections of 13 keratoacanthomas in comparison with 10 normal skin biopsies and 16 late-stage skin squamous cell carcinomas by counting and by computer-assisted image analysis of CD31-immunostained vessels. A significant increase of microvessel density in 'hot spots' was observed in keratoacanthomas as compared to normal skin. Furthermore, when keratoacanthomas were subdivided into tumours with and without malignancy-associated atypic areas, only those with atypia (n=6) were significantly better vascularised than normal skin and had a mean microvessel density in the range of late-stage squamous cell carcinomas. Both keratoacanthoma subtypes revealed comparable levels of inflammatory cell infiltration, tumour cell proliferation and vascular endothelial growth factor expression (mRNA and protein). Thus, in addition to malignancy-associated cellular atypia, increased microvessel density may serve as further diagnostic parameter to discriminate keratoacanthomas with a potential to progress to malignancy.