A 12 nucleotide oligodeoxyribopurine tract in the gene for the chemokine receptor CCR5 has been targeted and covalently modified in intact cells by a 12mer tripler forming oligonucleotide (TFO) bearing a reactive group, A nitrogen mustard placed on the 5'-end of the purine motif TFO modified a guanine on the DNA target with high efficiency and selectivity, A new use of a guanine analog in these TFOs significantly enhanced tripler formation and efficiency of modification, as did the use of the tripler-stabilizing intercalator coralyne. This site-directed modification of a native chromosomal gene in intact human cells under conditions where many limitations of tripler formation have been partially addressed underscores the potential of this approach for gene control via site-directed mutagenesis.