Background and Objectives: Treatment of photoaging and intrinsic aging of the chest, with the associated concerns of skin roughness, uneven pigmentation, laxity, atrophy, and telangiectasias, can be problematic because of the potential for worsened esthetic outcomes with existing treatments. This study assessed the efficacy and safety of using nonablative fractional laser therapy (FLT) pretreatment with photodynamic therapy (PDT) versus PDT alone for chest rejuvenation. Study Design/Materials and Methods: In a randomized, evaluator-blinded, split-sided study, adult female patients with photodamage to the chest received three treatment courses over an 8-week period with follow-up visits at Weeks 12 and 20. FLT was applied to one side of the chest, randomly assigned at baseline, followed by aminolevulinic acid-based PDT, delivered using a thermal, short incubation, broad area technique, to both sides of the chest. In-person and photographic assessments were conducted using fivepoint scales to evaluate outcomes including rhytides, pigmentation, skin texture, and telangiectasias. Results: Eleven adults completed the study, of whom 11 had improved scores for rhytides and 10 had improved scores for skin texture at Week 20. There was no significant difference in any efficacy outcome between FLT and PDT and standard PDT alone. The severity of adverse events was rated significantly greater with the combined FLT-PDT treatment vs PDT alone. Conclusions: Significant improvements were observed vs baseline for both sides of the chest treated with FLT-PDT or standard PDT following three treatment sessions. No significant difference in efficacy was observed between treatment approaches, although adverse events were more severe on the FLT-pretreated side. This study was not registered as it qualified as a nonsignificant risk study. Lasers Surg. Med.