Differences in preference-weighted health-related quality of life (HRQOL) scores by race/ethnicity may be due to social factors. Here, Short-Form Six-Dimension (SF-6D) scores are analyzed among men in a prostate cancer prevention trial to explore such differences. Selenium and vitamin E cancer prevention trial participants who completed the SF-6D at baseline, and in at least 1 of follow-up years 1, 3, and 5 were included. This study compared mean SF-6D scores across race/ethnicity at each point using a linear mixed model controlling for demographic and clinical characteristics. At baseline, 9691 men were eligible for analysis, of whom 7556 (78%) were non-Hispanic White, 1592 (16.4%) were non-Hispanic Black, and 543 (5.6%) were Hispanic. Hispanic and White participants had higher unadjusted mean SF-6D scores than Black participants at every time point (P < 0.05), while white participants had lower mean scores than Hispanic participants at every time point after baseline (P < 0.05). After adjusting for covariates, statistically significant differences in HRQOL among the 3 groups persisted. Hispanic participants had higher preference scores than White participants by 0.073 (P < 0.001), 0.075 (P < 0.001), and 0.040 (P < 0.001) in follow-up years 1, 3, and 5, respectively. Black participants had lower scores than White participants by 0.009 (P = 0.004) and 0.008 (P = 0.02) in follow-up years 1 and 3, respectively. The results suggest there is a preference-weighted HRQOL difference by race/ethnicity that cannot be explained by social and clinical variables alone. Understanding how individuals belonging to different racial/ethnic categories view their own HRQOL is necessary for culturally competent care and cost-effectiveness analyses.