Water-soluble derivatives of hypocrellins can be safely delivered in blood plasma but lose their photodynamic activity in vivo due to poor cell uptake, while hydrophobic derivatives retaining their activity may aggregate in the blood plasma and block vascular networks. Considering both drug delivery and biological activity, surfactant-like hypocrellin B (HB) derivatives, sodium 12-2-HB-aminododecanoate (SAHB) and sodium 11,11′-5,8-HB-dimercaptoundecanoate (DMHB), were first designed and then synthesized in the current work. Both SAHB and DMHB were photoactive, generating free radicals and reactive oxygen species, as confirmed by EPR and chemical measurements. Most importantly, DMHB was not only readily soluble, allowing preparation of an intravenous injection solution at a clinically acceptable concentration, but it was also more photodynamic therapy (PDT) active to human breast carcinoma MCF-7 cells than its parent HB under irradiation. The photodynamic activity was exactly identical to the 1O2 quantum yield and was not reduced by the improved water solubility, suggesting an independent hydrophilicity or lipophilicity. To our knowledge, this is a new strategy that possesses general significance for converting hydrophobic photosensitizers into clinically usable PDT drugs.