Background: Worldwide medical authorities recommend vitamin A supplementation for severe measles requiring hospitalization; however, evidence supporting its use in high-income countries is lacking. A nationwide vitamin A shortage reported in concomitance with a recent measles outbreak in Italy provided an opportunity to test the effectiveness of vitamin A in a high-income setting, approximating an unbiased allocation. Methods: We conducted a prospective controlled cohort study involving children admitted for measles to a tertiary-care hospital in Southern Italy. The primary outcome was the duration of fever. Secondary outcomes included the length of hospitalization, rate of complications, need for antibiotic treatment and body temperature. Results: A total of 108 inpatient children (36% female, median age 16.3 months) were enrolled; 36 received 2 doses of oil-based vitamin A according to age, and 72 matched controls received standard care. There were no significant differences between the study groups in the duration of fever (7.03 ± 2.67 vs. 6.82 ± 3.27, P = 0.72), length of hospitalization (median, 5.0 vs. 5.0 days, P = 0.50), maximum body temperature (median, 39°C in both groups, P = 0.23), rate of organ (69.4% vs. 63.9%, P = 0.72) and hematologic complications (41.7% vs. 59.7%, P = 0.12), or need for antibiotic treatment (66.7% vs. 61.1%, P = 0.72). Overall, vitamin A supplementation did not reduce the risk of any complications (relative risk, 1.33; 95% confidence intervals: 0.59–2.96). Conclusion: Vitamin A does not change the clinical course of measles infection or the rate of complications in children hospitalized in a high-income country. Study registration number: EU PAS 31805.