Objective: To compare the effect of natural oils and white petrolatum on skin barrier function in patients with xerosis.Design, Setting, and Participants: Randomized, open label, comparison pilot study (NCT03093597).Interventions: Participants were randomized to apply 1 of 4 moisturizers to assigned treatment areas twice daily for 2 weeks. Clinical dry skin score, stratum corneum hydration, and transepidermal water loss (TEWL) were assessed at baseline, 1 week, and 2 weeks.Results: Thirty-two participants completed the study. Neither TEWL nor hydration were statistically different among the moisturizers at each visit. All four moisturizers led to significant initial increase in TEWL at week 1 (p < 0.05) with an associated increase in hydration for coconut oil, jojoba oil, and white petrolatum. All four moisturizers led to significant increase in hydration by week 2 (p < 0.01). The preferred moisturizers were almond oil and coconut oil, which were most “liked” by 38% and 31% of the participants, respectively. The least preferred moisturizer was white petrolatum. Conclusions: Almond oil, jojoba oil, and coconut oil significantly increased hydration after 2 weeks, and are as effective as white petrolatum as daily moisturizers for xerosis. The participants preferred natural oils to white petrolatum, implying that these moisturizer options may improve patient compliance.