To determine whether psychopathology is associated with disability as a result of underlying physical illness or whether such psychopathology antedates disability and is an independent determinant of disability, the authors conducted a nested case-control study within the Epidemiologic Catchment Area Follow-up Study in Baltimore, Maryland. From a 1981 random sample of 3,481 persons from Baltimore interviewed for psychopathology, disability, and other comorbidity, 1,920 who were alive in 1993 were traced and were reinterviewed with a similar instrument. Within the study population, 168 new cases of disability were identified as occurring between 1981 and 1993, as measured by the inability to perform activities of daily living. These cases were compared with 1,715 controls who reported no disability. The sociodemographic factors that were significantly related to incident disability in this analysis were age, female gender, and less than a high school education. These comparisons revealed associations of incident disability in activities of daily living with almost all antecedent chronic physical illnesses. Significant age- and gender-adjusted associations were observed between incident disability in activities of daily living and antecedent (in 1981) alcohol abuse and dependence (odds ratio (OR) = 2.5, 95% confidence interval (CI) 1.5–4.2), major depressive disorder (OR = 4.2, 95% CI 2.2–8.3), and phobia (OR = 1.9, 95% CI 1.3–2.8). The adjusted odds ratio for the joint effect of antecedent depression and chronic physical illness on incident disability in activities of daily living was 17.0 (95% CI 6.9–41.7). There was a significant independent effect of antecedent major depression on activities of daily living disability. The effect of psychopathology on incident disability is nonspecific as to type of baseline chronic physical illness. Such a finding has important implications for defining strategies to prevent disability. Am J Epidemiol 1998;148:269–75.