Hyperpigmentation is a cosmetically important condition that can arise from a variety of sources, including exposure to UV light or photosensitizing agents. Although topical hydroquinone (HQ) has been the gold standard of treatment for hyperpigmentation, it is associated with potential carcinogenicity and has irritative properties that can complicate treatment. Accordingly, alternate depigmentation formulations that do not contain hydroquinone are becoming of increasing interest. This study was undertaken in an effort to determine whether a non–HQ-containing formulation could provide depigmentation comparable with or better than a formulation containing HQ. Accordingly, this paper reports on a study comparing a natural-based, HQ-free, physician-dispensed bleaching cream with an HQ 4% bleaching gel in a blinded, split-face study over an 8-week period for depigmentation. Twenty-one women, aged 20 to 75 years, were randomized to receive either a natural-based bleaching cream that did not contain HQ or an HQ 4% bleaching gel. Subjects were given samples labeled A and B, which were randomly assigned to either the left or the right side of the face. The subjects were instructed to apply the products twice a day, in the morning and evening, for 8 weeks. Subjects were required to use a cleanser prior to applying either product and were instructed to apply sunscreen following product application in the morning only. Subjects were evaluated by an expert grader for fine lines, wrinkles, skin roughness, and reduction in hyperpigmentation at baseline (week 0) and at weeks 4 and 8 after study initiation. Digital photographs were also taken at these time points to perform red/brown image analysis. Skin pigmentation was assessed by the expert grader on a 3-point scale, with 21 indicating unfavorable darkening change; 0 indicating no change; and 11 indicating favorable lightening change. Review of the images, along with expert grading, revealed decreased hyperpigmentation in 89% of subjects using the natural-based bleaching cream and 83% of subjects using the HQ 4% bleaching gel. Average scores were 0.83 for the natural-based bleaching cream and 0.78 for the HQ 4% bleaching gel. Qualitative assessment of fine lines, wrinkles, skin roughness, and hyperpigmentation by the expert grader corroborated these trends. For the entire 8-week study period, the reduction in hyperpigmentation was 70% for the cream and 63% for the gel. Similar trends with regard to reduced hyperpigmentation were observed in another study (n=12) at a different site. On the measure of skin roughness, there was a 61% reduction with the natural-based bleaching cream compared with 66% with the HQ 4% bleaching gel. Image analysis for erythema (redness) indicated that 67% of subjects using the natural-based bleaching cream experienced irritation, compared with 83% of subjects who used the HQ 4% bleaching gel. Average scores, based on the 3-point scale previously mentioned, were 20.56 for the natural-based bleaching cream and 20.67 for the HQ 4% bleaching gel. The results indicate that the natural-based bleaching cream produced a more pronounced reduction in hyperpigmentation compared with the HQ 4% bleaching gel. Furthermore, erythema was not as positively affected with the HQ 4% bleaching gel. This study suggests that the natural-based bleaching cream is equal to or better than the HQ 4% bleaching gel, both in terms of reducing hyperpigmentation and with regard to greater tolerability.