<p>The prevalence of monoclonal gammopathy of undetermined significance (MGUS) increases with age, but the study of age of onset and the prevalence of MGUS in younger individuals has been limited by lack of sensitive serum protein testing methods. In addition, there is marked racial disparity in the prevalence in Black individuals compared with White individuals and it is important to determine if MGUS has an earlier age of onset in Black individuals. In this first large mass spectrometry-based population-based screening study of MGUS, we evaluated 12,378 individuals (3598 White, 4075 Black, 4147 Mexican Americans, and 558 others) aged 10–49 years of age. The study used serum samples from the National Health and Nutritional Examination Survey (NHANES) III. MGUS was identified in 177 persons (1.28%, 95% CI 0.95, 1.60). MGUS was detectable in 0.2% of individuals age 10–19 years and the prevalence increased with age to 0.88%, 1.46%, and 2.82% in individuals ages 20–29, 30–39, and 40–49, respectively. The age-adjusted prevalence of MGUS was significantly higher in Black individuals compared with White individuals, 1.49% (1.13, 1.95) versus 0.82% (0.57, 1.18), <i>P</i> = &lt; 0.01. MGUS had an earlier age of onset in Black individuals; the increased prevalence of MGUS among Black compared with White individuals was apparent at age 30–39 years, 2.94% vs 1.42%, and this disparity increased further in the age group 40–49 years to 5.2% vs 2.8%, respectively. There was no significant difference in the prevalence of MGUS between White individuals and Mexican American individuals in the overall cohort, or within any specific age group. The study using a highly sensitive mass spectrometry-based assay demonstrates onset of monoclonal gammopathy in the second decade of life, with a higher prevalence among the Black individuals with comparable prevalence among the White and Mexican individuals, a disparity that increases with advancing age.</p>