Unemployment has been associated with poor psychologic well-being. Using data from the 2001 Behavioral Risk Factor Surveillance System, we examined relationships between unemployment and frequent mental distress (FMD), defined as 14 or more mentally unhealthy days during the previous 30 days, among 98,267 men and women aged 25-64 years. The age-standardized prevalence of FMD was 6.6% (standard error, 0.14) among employed adults, 14.0% (2.00) among adults unemployed >1 year, and 15.5% (1.18) among those unemployed <1 year. After adjustment, the relative odds of FMD were 2.09 (95% confidence interval [CI] = 1.75-2.50) for adults unemployed <1 year and 1.88 (95% CI = 1.31-2.71) for adults unemployed >1 year compared with employed adults. Similar patterns were observed across gender, race/ethnicity, education, income, and area unemployment groups. Unemployed persons are a population in need of public health intervention to reduce the burden of mental distress. Public health officials should work with government officials to incorporate the health consequences of unemployment into economic policymaking.