We have discovered that antimicrobial photodynamic inactivation (aPDI) can be strongly potentiated by addition of the non-toxic salt potassium iodide. This approach works with a wide variety of different photosensitizers including those possessing cationic charges that bind to microbial cells, and those neutral or anionic compounds that are completely ineffective in photoinactivating Gram-negative cells, but can kill > 6 logs in presence of 100 mM KI. The approach is broad spectrum in nature and works with MRSA, a range of Gram-negative bacteria and Candida. The major mechanism is likely to involve the addition of singlet oxygen to iodide to form peroxyiodide, which then decomposes via two possible routes: (a) formation of the stable species, free iodine and hydrogen peroxide; (b) formation of short-lived radicals I2•- + HOO•. When the PS binds to the microbial cells, killing by the short-lived radicals becomes significant, while for Gram-negative cells with Photofrin or Rose Bengal, killing by I3- and H2O2 are dominant. This can be studied by comparing “in” (all ingredients together, “after” cells added after light, and “spin” KI and light added after cells were incubated with PS and centrifuged. We have recently studied two porphyrins TMPyP4 (tetracationic) and TPPS4 (tetraanionic). Surprisingly TPPS4 was an excellent PS for MRSA and Candia, and could eradicate Gram-negative species when KI and light were added after a spin, showing it was bound to the surface. Another tetraanionic phthalocyanine (ClAlPCS4) did not show this behavior. We conclude that TPPS4 behaves as if it has some cationic character in the presence of bacteria. KI could potentiate RB-PDT in a mouse model of skin abrasions infected with bioluminescent P. aeruginosa demonstrating possible in vivo applications.