Positronium annihilation lifetime (PAL) experiments have been performed to investigate the interaction between skin cancer and positronium for human skin samples under wet and dried conditions. PAL analysis for pairs of human cancer skin samples shows that positronium annihilation lifetime is shorter and ortho-positronium intensity is less for the samples with basal cell carcinoma and squamous cell carcinoma than the normal skin samples under both conditions. These results indicate a reduction of free volume in the molecular level for the skin with cancer compared with the result for the skin without cancer. Positron annihilation spectroscopy may be potentially developed as a new non-invasive and external method for dermatology clinics, early detection of cancer, and nano-PET technology in the future.