Nordihydroguaiaretic acid (NDGA, meso-1) possesses four phenolic hydroxyl groups. Treatment of NDGA with 0.50-4.1 equiv of dimethyl sulfate and 3.0-6.0 equiv of potassium carbonate in acetone at 56 degrees C gave nine methylated products. Eight of those mono-, di-, tri-, and tetra-O-methylated NDGAs were isolated in pure form, and their structures were identified unambiguously by spectroscopic methods. A preparative amount of tetramethyl NDGA M4N (10) was obtained in 99% yield from NDGA by use of 4.1 equiv of dimethyl sulfate for the methylation. Among the eight different methylated NDGAs (2-6 and 8-10), tetra-O-methyl-NDGA (10) showed the strongest anti-HIV activity (IC50 11 microM). Chemically synthesized 3'-O-methyl-NDGA ((+/-)-2) showed identical anti-HIV activity (IC50 25 microM) to the lignan isolated from Creosote Bush. Lignans with methylated catecholic hydroxyl groups can be produced in large quantities with low cost. At drug concentrations below 30 microM tetramethyl NDGA (10) was a stronger anti-HIV agent than mono- and dimethylated NDGAs.