Cationic porphyrins such as meso-tetrakis(4-(N-methylp,yridiumyl))porphyrin. or H(2)T4. are remarkably versatile DNA binding agents of interest for potential therapeutic applications. This study focuses on the influence the DNA bases have in determining, the mode of uptake and the relative binding affinity. For convenience the host is usually a DNA hairpin formed spontaneously by a 16-mer with the sequence 5'-GAXYACTTTTGTY'X'TC-3', where X and Y designate varying nucleotides with complements X' and Y'. Results from absorbance, emission, and CD spectroscopies lead to several conclusions, Among these is the recognition that the base composition, far more than the base sequence, dictates the mode of binding. Thus, any run of DNA containing at least 50% G=C base pairs supports intercalative binding,imply because a robust hydrogen-bonding framework (1) stabilizes the intercalated adduct, and (2) inhibits distortions that fa or external binding. Another striking finding is that there is hardly any difference in binding constant for a hairpin that supports intercalation as compared with one that supports external binding, despite the host of factors that go into the energy, balance. Finally, in and of itself, the steric bulk of the th mine inethyl group does not prep ent HJ4 from intercalating in A=T-rich regions of DNA because uridine-for-thyrnine base replacement has no effect on adduct formation.