Purpose <p>To clinically evaluate dermal thickness, pores, and wrinkles after using Profhilo® in perioral regions.</p> Materials and Methods <p>This split-face study included 12 female participants aged 45 to 65 with visible signs of perioral aging. After selection, a blinded operator randomly allocated the right and left sides to receive either treatment (experimental group—Profhilo®) or placebo (control group—saline solution). Treatment consisted of two sessions spaced 30&#xa0;days apart. For the first session, 3 points were marked on the cutaneous portion of the upper lip and 2 points on the lower lip, at 5&#xa0;mm from the beginning of the mucosa, for each side of the face. The amount of product injected in each session was 1 ml of Profhilo®. The same proportion of saline solution was used on the opposite side of the upper and lower lips, following the same application points. After 30&#xa0;days, a local evaluation and application of the second session were performed, following the same protocol as the first. At 60&#xa0;days, digital stereophotogrammetry, ultrasound of the perioral region, and standardized photographic images were performed. In addition, the volunteers answered the Face-Q questionnaire to assess satisfaction with the treatment, signs of aging, post-procedure recovery, and psychological factors. Subsequently, the data collected were tabulated and analyzed using paired t-test and Wilcoxon test, with a significance level of 5%.</p> Results <p>Stereophotogrammetry revealed visual improvements in wrinkles and pores after the application of Profhilo®. Ultrasonography indicated an increase in dermal thickness for both Profhilo® (<i>p</i> = 0.016) and placebo (<i>p</i> &lt; 0.001). A substantial proportion of participants expressed dissatisfaction with the decision to undergo treatment (36.4%) and the treatment outcomes (54.5%). Most participants reported mild recovery symptoms, with only one noting extreme sensitivity, discomfort, and itching. The intervention evaluated psychological function, appearance, and aging, which resulted in statistically significant improvements in psychological scores (<i>p</i> = 0.014) and aging assessment (<i>p</i> = 0.008).</p> Conclusion <p>Profhilo® reduced wrinkles and pore size; however, its impact on dermal thickness did not exceed the placebo effect, and patients were not fully satisfied with outcomes.</p> Level of Evidence I <p>This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors <a href="http://www.springer.com/00266">www.springer.com/00266</a>.</p>