Background There is a rationale for adding systemic photoprotective agents to the current photoprotection regimen. Objective This study was designed to objectively evaluate the molecular and photobiologic effects of oral administration of Polypodium leucotomos extract (PLE). Methods In all, 22 subjects with Fitzpatrick skin phototype I to III were enrolled. On day 1, subjects were irradiated with visible light, ultraviolet (UV) A1, and UVB (using 308-nm excimer laser). Evaluation was done immediately and 24 hours after irradiation. On days 3 and 4, irradiation and evaluation process was repeated after ingestion of PLE. Results Clinical assessments and colorimetry data showed a decrease in UVB-induced changes in 17 of 22 subjects post-PLE administration; histology findings demonstrated such a decrease in all 22 subjects. Limitations Only 2 doses of PLE were given. Furthermore, subjects with skin phototypes I to III only were studied. Conclusion The results suggest that PLE can potentially be used as an adjunctive agent to lessen the negative photobiologic effects of UVB.