The association of lead toxicity with delta -aminolevulinic acid dehydratase (ALAD) and vitamin D receptor gene polymorphisms was examined in 216 workers occupationally exposed to lead. Urinary N-acetyl- beta-glucosaminidase (UNAG) activity and albumin concentration, adjusted by creatinine, were measured as biomarkers of nephrotoxicity. Genotyping was performed using polymerase chain reaction and restricted fragment length polymorphisms. Blood pressure and blood and urinary lead concentrations were measured. No statistically significant difference in blood lead concentrations was observed with the ALAD genotype, although the geometric mean of blood lead concentrations was higher in battery workers with the ALAD-12 genotype (50.95 mug/dL) than in workers with the ALAD-11 genotype (42.95 mug/dL). Battery workers with the vitamin D receptor (VDR)-B allele had higher mean blood lead concentrations (60.54 mug/dL) than did the workers with the VDR-bb genotype (51.65 mug/dL) (p <. 05) . Based on multiple linear regression analysis, the VDR genotype was associated with a blood lead level (p <. 021). The ALAD genotype was associated with a urinary lead level (p <. 009). Workers with the ALAD-12 genotype who also had blood lead concentrations equal to or greater than 40 mug/dL had higher UNAG activity (4.17 U/mmol.Cr) than the workers with the ALAD-11 genotype (1.27 U/mmol.Cr) (p =. 06). Compared with workers with the VDR-bb genotype, workers with the VDR-B allele had higher systolic blood pressure when the blood lead level was equal to or greater than 40 mug/dL (133.06 +/- 19.19 mmHg versus 123.12 +/- 15.69 mmHg, p =. 01). Lead workers with ALAD-12 had larger elevations in UNAG activity and increasing blood lead concentrations compared to lead workers with the ALAD-11 genotype. Lead workers with the VDR-B allele had greater elevations in systolic blood pressure and higher blood lead levels than did workers with the VDR-bb genotype. In summary, the ALAD-2 and VDR-B alleles may modify lead absorption and toxicity.