Moisturizers have beneficial effects in treating dry skin. The objective of this study was to evaluate the effect of orange roughy (Hoplostethus atlanticus) oil, a marine-derived wax ester, on skin dryness in comparison with a reference commercially available petrolatum-based moisturizer (Vaseline) and untreated control. Subjects (n = 24) with moderate to severe skin dryness at the lower limb of legs (Study 1) and with certain degree of skin dryness on the face and the forearms (n = 22, Study 2) were treated twice a day for 42 consecutive days with the test products in randomized clinical trials. Transepidermal water loss (TEWL) was measured at the beginning and the end of Study 1, whereas skin hydration was measured at the beginning, after 3 and 6 weeks of the application (the end of the study) in Study 2. Changes in the skin dryness were assessed by a dermatologist using a video microscopy. In Study 1, the dryness score of skin applied with orange roughy oil improved significantly (P < 0.01) in 6 weeks. The skin looked smooth with no or little dry scaly skin. Orange roughy oil was evaluated with a 60% efficacy in treating skin dryness by the expert, which comparable to that of petrolatum (68%). No significant change in TEWL was found either in orange roughy oil or petrolatum treatment, although the values showed a tendency to improve in both cases. Similarly, the results of the skin capacitance in Study 2 showed a significant improvement of the skin symptoms after 3 and 6 weeks. These results showed that the performance of orange roughy oil in treating skin dryness was comparable to that of petrolatum.