BACKGROUND: Mesotherapy treatment of aging skin aims to replace depleting levels of minerals, vitamins, amino acids, and hyaluronic acid (HA). AIM: To investigate the efficacy of 13.5 mg/g uncross-linked HA+0.9% mannitol (HA+mannitol) on skin hydration and elasticity. PATIENTS/METHODS: Four centers enrolled 34 women: Subgroup 1 comprised 27 subjects injected using a "depot" technique; Subgroup 2 comprised seven subjects injected using a "picotage" technique. RESULTS: A notable difference was seen between the two subgroups in outcome and subject satisfaction. In Subgroup 1, a significant improvement was seen in hydration, anisotropy, and skin roughness, but Subgroup 2 showed no significant improvements. Most physicians assessed HA+mannitol as "easy/very easy" to inject. Physician esthetic assessment in Subgroup 1 was "improved/very improved" for >90% of subjects at Day 60, and >80% according to subject assessment. 95% of subjects were delighted with treatment, and 85% would undergo repeat treatment and would recommend treatment to a friend. However, results for Subgroup 2 indicated 86% of subjects were unhappy with treatment and 83% would refuse to undergo repeat treatment. CONCLUSIONS: HA+mannitol is effective for skin hydration, anisotropy, and roughness when treated using a depot technique.