The objective of the current study was to investigate the influence of cyclodextrin complexation on the in vivo photoprotective effects of a model ultraviolet (UV) absorber, oxybenzone, and to compare these novel sunscreens to a commercial SPF 30 sunscreen product. Aqueous-based solutions and suspensions containing 2.7 mg/mL oxybenzone and up to 20% (w/w) hydroxypropyl-beta-cyclodextrin (HPCD) were prepared. The sunscreens were applied to the dorsal skin of SKH-1 hairless mice and the animals were exposed to up to two minimal erythemal doses (MEDs) of UV radiation. Control animals received no sunscreen treatment. Lipid damage, as quantified by decreases in the lipid melting temperature of the epidermis, was determined using differential scanning calorimetry immediately after UV exposure. The number of sunburn cells (SBCs) and the extent of edema were measured 24 hours postexposure. Results showed that all oxybenzone-containing formulations decreased the number of SBCs formed, diminished swelling, and reduced the physical damage to the skin structure, in comparison to control. Thus, complexation did not prevent oxybenzone from reacting with light. The 20% HPCD formulation exhibited more substantial photoprotection at UV exposures of one or two MEDs, as evidenced by the formation of fewer SBCs. The 5% HPCD formulation also provided substantial protection against epidermal lipid damage. These studies demonstrate that inclusion of HPCD in sunscreen formulations may enhance the in vivo photoprotective effects of the UV absorbers. No single HPCD-containing sunscreen, however, was found to be equivalent to a commercially available sunscreen product for all biomarkers investigated.