BACKGROUND/OBJECTIVES: Vitamins D and B12 play a crucial role in maintaining bone health, immune function, and neurological integrity. Combined deficiencies in these vitamins can lead to severe health consequences. Current treatment approaches, such as dietary changes and single-vitamin supplementation, often fail to address these deficiencies comprehensively. This study evaluates the effectiveness of concurrent vitamin D and B12 supplementation to correct these insufficiencies. METHODS: A prospective, multicenter, randomized controlled trial was conducted in Greece from October 2024 to December 2024. Participants aged 20 to 80 years, with insufficient levels of 25-hydroxyvitamin D (serum <
20 ng/mL) and B12 (serum <
250 ng/L), were eligible for inclusion. RESULTS: A total of 124 patients were randomized into three groups: one receiving vitamins B12 and D in a single supplement (2500 IU + 1000 mcg), one receiving separate doses of each vitamin (2000 IU + 1000 mcg), and a control group receiving no supplementation. The results demonstrated a significant increase in B12 and 25-hydroxyvitamin D levels among the supplemented groups. Particularly, participants in the combined supplementation group showed higher average serum levels of both vitamins. By the end of this study, 37.1% of those in the combined supplement group achieved adequate vitamin levels, compared to 29.4% in the separate supplementation group. CONCLUSIONS: In conclusion, combined supplementation may improve patient adherence and compliance, leading to better health outcomes for individuals with combined vitamins D and B12 deficiencies.