BACKGROUND: Unique whole formula nature-based sensitive skin products are formulated to minimize irritation while providing conditioning and soothing benefits to clinically diagnosed sensitive skin. OBJECTIVE: To evaluate and compare the efficacy and tolerability of a regimen of cleanser containing natural oils, beeswax, and witch hazel, and day & night creams containing natural oils, glycerin, and botanical anti-inflammatories (NR); and a synthetic dermatologist-recommended regimen of cetyl alcohol, sodium lauryl sulphate-containing cleanser and glycerin, polyisobutene-containing lotion (CR) in clinically diagnosed sensitive skin resulting from eczema/atopic dermatitis, rosacea, or cosmetic intolerance. METHODS: 120 subjects were randomized to receive either NR or CR, twice daily for 4 weeks in this double-blind study. Blinded investigator-rated and subject-rated overall skin appearance was assessed using a 5-point scale (0=none, 4=severe) at baseline, 2 weeks, and 4 weeks. Noninvasive skin assessments for skin hydration and skin barrier function were made by corneometry and TEWL, respectively. RESULTS: NR resulted in a 34% improvement from baseline in investigator-rated overall skin appearance (P less than 0.001); and CR resulted in a 4% improvement. Similar NR and CR results were found in the other efficacy parameters: tactile and visual smoothness, clarity, and radiance. Both regimens improved barrier function from baseline to week 4 (17%, 15%; NR, CR, P equals NS). NR maintained hydration from baseline to week 4 while CR increased hydration by 21% (P less than 0.001). No clinically significant tolerability issues were reported in either regimen at week 4. CONCLUSIONS: The study demonstrated that NR was effective, well tolerated, and superior to CR in the management of sensitive skin. J Drugs Dermatol. 2018;17(8):908-913.