Cutaneous squamous cell carcinoma (cSCC) arising from the malignant proliferation of epidermal keratinocytes is the second most common skin cancer. Actinic keratosis (AK), which is considered cSCC in situ, may progress into invasive tumors. Currently, there are no serum markers that can differentiate cSCC from AK. The aim of our study was to assess angiogenesis and oxidative stress in patients with cSCC and patients with AK and find reliable serum markers useful in the diagnosis of cSCC. We have determined the serum levels of a group of proangiogenic factors (MMP-2, MMP-9, VEGF, FGF2), the total antioxidative status/capacity (TAS/TAC), ImAnOx, a marker of oxidative stress, and HIF-1 alpha, an indicator of hypoxia. We have identified higher serum levels of MMP-2. MMP-9, VEGF, FGF2 and HIF-1 alpha and lower levels of ImAnOx in cSCC patients compared to AK patients and controls. There were no statistically significant differences between AK patients and controls. We have found positive correlations between proangiogenic markers and HIF-1 alpha and negative correlations between proangiogenic markers and ImAnOx. Our results suggest that MMP-2, MMP-9, VEGF, FGF2, ImAnOx and HIF-1 may be promising markers for differentiating AK from cSCC, and there is a link between angiogenesis, oxidative stress and hypoxia.