Photoacoustic imaging (PAI) shows promise for skin cancer diagnosis by detecting chromophores like melanin, hemoglobin, lipids, and collagen. While most studies focus on malignant lesions, understanding normal skin variability across anatomical regions is crucial for validating PAI's clinical application and its use in melanoma diagnosis. We assessed normal skin in 20 healthy volunteers from three different body locations using a clinical PAI system and compared suspicious looking pigmented skin lesions, including melanomas, to adjacent normal skin (n = 74). Higher deoxyhemoglobin levels were observed in the ankle compared to the cheek and volar forearm, while melanin, lipids, and collagen showed minimal variation. Patients with malignant lesions had significantly higher deoxyhemoglobin levels (p = 0.001) than adjacent normal skin, a difference not seen in benign lesions. These findings suggest that PAI may help diagnose malignancies by identifying increased vascularity in skin cancers, while anatomical differences should be considered during diagnostic work-up.