Although work performance has become an important outcome in cost-of-illness studies, little is known about the comparative effects of different commonly occurring chronic conditions on work impairment in general population samples. Such data are presented here from a large-scale nationally representative general population survey. The data are from the MacArthur Foundation Midlife Development in the United States (MIDUS) survey, a nationally representative telephone-mail survey of 3032 respondents in the age range of 25 to 74 years. The 2074 survey respondents in the age range of 25 to 54 years are the focus of the current report. The data collection included a chronic-conditions checklist and questions about how many days out of the past 30 each respondent was either totally unable to work or perform normal activities because of health problems (work-loss days) or had to cut back on these activities because of health problems (work-cutback days). Regression analysis was used to estimate the effects of conditions on work impairments, controlling for sociodemographics. At least one illness-related work-loss or work-cutback day in the past 30 days was reported by 22.4% of respondents, with a monthly average of 6.7 such days among those with any work impairment. This is equivalent to an annualized national estimate of over 2.5 billion work-impairment days in the age range of the sample. Cancer is associated with by far the highest reported prevalence of any impairment (66.2%) and the highest conditional number of impairment days in the past 30 (16.4 days). Other conditions associated with high odds of any impairment include ulcers, major depression, and panic disorder, whereas other conditions associated with a large conditional number of impairment days include heart disease and high blood pressure. Comorbidities involving combinations of arthritis, ulcers, mental disorders, and substance dependence are associated with higher impairments than expected on the basis of an additive model. The effects of conditions do not differ systematically across subsamples defined on the basis of age, sex, education, or employment status. The enormous magnitude of the work impairment associated with chronic conditions and the economic advantages of interventions for ill workers that reduce work impairments should be factored into employer cost-benefit calculations of expanding health insurance coverage. Given the enormous work impairment associated with cancer and the fact that the vast majority of employed people who are diagnosed with cancer stay in the workforce through at least part of their course of treatment, interventions aimed at reducing the workplace costs of this illness should be a priority.