The authors evaluated the association between lead burden and psychiatric symptoms and its potential modification by a delta-aminolevulinic acid dehydratase (ALAD) polymorphism. Lead measurements in blood or bone and self-reported ratings on the Brief Symptom Inventory from 1991 to 2002 were available for 1,075 US men participating in the Department of Veterans Affairs (VA) Normative Aging Study. The authors estimated the prevalence odds ratio for the association between interquartile-range lead and abnormal symptom score, adjusting for potential confounders. An interquartile increment in tibia lead (14 microg/g) was associated with 21% higher odds of somatization (95% confidence interval of the odds ratio: 1.01, 1.46). An interquartile increment in patella lead (20 microg/g) corresponded to a 23% increase in the odds of global distress (95% confidence interval of the odds ratio: 1.02, 1.47). An interquartile increment in blood lead (2.8 microg/dl) was associated with 14% higher odds of hostility (95% confidence interval of the odds ratio: 1.02, 1.27). In all other analyses, lead was nonsignificantly associated with psychiatric symptoms. The adverse association of lead with abnormal mood scores was generally stronger among ALAD 1-1 carriers than 1-2/2-2 carriers, particularly regarding phobic anxiety symptoms (p(interaction) = 0.004). These results augment evidence of a deleterious association between lead and psychiatric symptoms.