Antimicrobial photodynamic therapy is emerging as a promising therapeutic modality for bacterial infections. Our studies aim at identifying strategies for optimizing the antibacterial activity of porphyrin-type photosensitisers. The photoinactivation properties of a novel, positively charged meso-substituted porphyrin, namely 5-[4-(1-dodecanoylpyridinium)]-10,15,20-triphenyl-porphyrin were tested against a typically antibiotic-resistant pathogen, such as methicillin-resistant Staphylococcus aureus. This porphyrin is characterized by an unusually large quantum yield (0.95) for the generation of the hyper-reactive oxygen species, singlet oxygen. In spite of this, it exhibits a relatively low photosensitising activity against bacteria when dissolved in a homogeneous aqueous solution or incorporated into neutral lipid vesicles. On the contrary, a dramatic potentiation of the photocydal effect takes place when polycationic agents such as liposomes of N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride are used as carriers. The cationic carrier primarily acts as a disorganizing agent for the native three-dimensional architecture of the bacterial wall, thereby enhancing its permeability to the photosensitiser. Consequently, the drug can deeply penetrate into the plasma membrane, and rapidly impair selected enzymic activities leading to cell death. Thus, the combination of positively charged drugs and cationic delivery systems appears to represent an innovative modality for achieving an efficient antimicrobial activity and opens new avenues for the development of this phototherapeutic application.