Purpose: To characterize the nuclear oxalate binding protein and its involvement in hyperoxaluria. Materials and Methods: Rat and human renal cortical epithelial cell nuclear protein was isolated and studied. Renal nuclear histones were isolated by acid extraction and purified by ion exchange column chromatography. Results: Most of the 14C-oxalate binding was present in the histone-H1 fraction. The oxalate binding activity resided exclusively in the H1B fraction of H1. The protein was purified 13 to 16- fold with a specific activity of 940 to 1570 pmol./mg. protein. Oxalate binding to rat or human kidney or calf thymus histone was rapid, reversible, pH dependent and saturable. Trypsin treatment abolished the binding activity. Scatchard plot analysis revealed the presence of 2 distinct oxalate binding sites, one with high affinity and the other with low affinity. Oxalate binding was inhibited by DIDS (4,4'-diisothio-cyanostilbene-2, 2'-disulfonic acid) and other dicarboxylate transport inhibitors. The IC50 values for different substrate analogues were, in decreasing order, oxalate < oxamate < succinate < glyoxylate < malate < glycolate. In experimental urolithic rats, histone oxalate binding was increased by 50 to 70%. The higher oxalate binding activity in hyperoxaluric rats was due to increased formation of H1. Histone exhibited in vitro calcium oxalate crystal growth promoter activity. Conclusion: Oxalate binding activity resided in the H1B of histone H1. The protein promoted calcium oxalate crystal growth. This suggested a possible role for this protein in the retention of calcium oxalate in the nucleus.