OBJECTIVES: Relationships between health insurance status and health-related quality of life (HRQOL) were investigated. METHODS: The 2000 Medical Expenditure Panel Survey data were analyzed to examine relationships between health insurance status and health-related quality of life. HRQOL was measured using the SF-12 Physical Component Summary (PCS) and SF-12 Mental Component Summary (MCS). The sample included adults aged 25 to 64 years who did not have Medicaid or Medicare coverage. Respondents who were insured for only part of the year were excluded from the analysis. Survey weighted multiple regression models using SAS version 8.2 were used for the analysis. The analysis controlled for sociodemographic variables, attitudinal variables and medical conditions. The analysis also investigated and controlled for the possible endogeneity of the health insurance status variable in the models. RESULTS: Of the 8141 adults in the sample that met inclusion criteria, 1449 (17.79%) were without health insurance for the entire year. Tests were positive for endogeneity of the health insurance status in PCS model but not in the MCS model. After adjusting for covariates that included age, gender, race, education, income, attitude towards the value of health insurance and health care, and presence or absence of each of nine reported medical conditions, individuals without health insurance had significantly lower PCS scores than those with health insurance. Individuals with family income above 200% of federal poverty level had a higher detrimental effect of absence of health insurance on PCS compared to individuals with family income below 200% of federal poverty level (Beta=-10.85 versus Beta=-8.21). The adjusted adverse effect of no health insurance also was significant in the MCS model (Beta=-1.43; SE=0.49). CONCLUSION: The detrimental effect of lack of health insurance on HRQOL equals or exceeds the detrimental effect of many serious medical conditions on HRQOL.