•XMEN disease involves intracellular Mg2+ deficiency, impaired EBV control, and high risk of lymphoma.•Ugandan women with poorly controlled EBV infection and children with Burkitt lymphoma were more likely to have low plasma Mg2+.•Cellular uptake of Mg2+ by lymphocytes from healthy donors correlates with extracellular Mg2+ concentration.•Reduced plasma Mg2+, perhaps due to dietary deficiency, may impair EBV control and increase the risk of Burkitt lymphoma in Africa. Epstein-Barr virus (EBV) causes endemic Burkitt lymphoma (eBL). EBV control was improved by magnesium (Mg2+) supplementation in XMEN, an X-linked genetic disease associated with Mg2+ deficiency, high circulating EBV levels (viral loads), and EBV-related lymphomas. We, therefore, investigated the relationship between Mg2+ levels and EBV levels and eBL in Uganda. Plasma Mg2+ was measured in 45 women with low or high circulating EBV levels, 40 pediatric eBL cases, and 79 healthy children. Mg2+ uptake by T-lymphocytes was evaluated in samples from healthy donors. Plasma Mg2+ deficiency (plasma level <1.8 mg/dl) was more likely in women with high- vs. low-EBV levels (76.0% vs. 35%; odds ratio OR 11.3, 95% CI 2.14–60.2), controlling for age, and in eBL cases than controls (42.0% vs. 13.9%; OR 3.61, 95% CI 1.32–9.88), controlling for sex, age group, and malaria status. Mg2+ uptake by T-lymphocytes was related to extracellular Mg2+ concentration. Plasma Mg2+ deficiency is associated with high EBV levels and eBL.