Phthalocyanines (Pcs) are a class of photosensitizers (PSs) with a strong tendency to aggregate in aqueous environment, which has a negative influence on their photosensitizing ability in photodynamic therapy. Pcs with either peripheral or axial solketal substituents, that is, ZnPc(sol) 8 and Si(sol) 2 Pc, respectively, were synthesized and their tendency to aggregate as well as their photodynamic properties in 14C and B16F10 cell lines were evaluated. The results were compared to more hydrophilic silicon Pcs, that is, Si(PEG750) 2 Pc and Pc4. The order of cellular uptake was Pc4 > ZnPc(sol) 8 > Si(PEG750) 2 Pc > Si(sol 2 )Pc. In contrast, Si(sol 2 )Pc showed the highest photocytotoxicity, while ZnPc(sol) 8 did not show any photocytotoxicity up to a concentration of 10 µM in both cell types. UV/vis spectroscopy showed that Si(sol) 2 Pc is less prone to aggregation than ZnPc(sol) 8 , which can explain the lack of photoactivity of the latter. Si(sol) 2 Pc was predominantly located in lipid droplets, whereas Si(PEG750) 2 Pc was homogeneously distributed in the cytosol, which is probably the main cause of their difference in photoactivity. The very high photodynamic efficacy of Si(sol) 2 Pc makes this PS an interesting candidate for future studies.