Understanding influences on health-related quality of life (HRQL) is critical in order to track and improve the health of poor, vulnerable populations and reduce health disparities. However, studies assessing HRQL of minorities are relatively scarce. The purpose of this study was to document personal and socioenvironmental correlates to HRQL. The study population is Mexican Americans in the Texas-Mexico border region living in colonias - unincorporated, impoverished settlements with substandard living conditions along the U.S.-Mexico border. Mexican Americans living in colonias are one of the most disadvantaged, hard-to-reach minority groups in the United States. We used data from the Integrated Health Outreach System Project collected in 2002 and 2003. Our sample included 386 participants randomly selected and interviewed face-to-face with a structured survey. We measured HRQL and examined personal and socioenvironmental correlates. Unadjusted and adjusted (multivariate) logistic regression models were used for data analyses. We found that border Mexican Americans living in colonias were of similar mental health status compared to the general population of the United States, but worse off in terms of physical health. Poor education and long-term residency in colonias were predictors of lower physical health. Women reported worse mental health than men. Length of time living in a colonia, co-morbidity status, and perceived problems with access to healthcare was associated with poorer mental health status. This study provides information for health professionals and policymakers and underscores the need to provide better preventive and medical services for underserved populations. Major findings indicate the need for additional research centered on further exploration of the impact of economic, cultural, and social influences on HRQL among severely disadvantaged populations.