In general, de novo solid tumors are composed of phenotypically and functionally heterogeneous malignant cells. This heterogeneity interferes with the effectiveness of targeted molecular cancer therapies. Even if most of the tumor is killed by a targeted treatment, recurrences are common and can be lethal. In this study, a mixed tumor model, which is predominantly a population of epidermal growth factor receptor (EGFR)-positive A431 cells combined with a smaller population of EGFR-negative Balb3T3/DsRed cells, was established. This mixed tumor was then treated with photoimmunotherapy, a newly developed target-cell-selective cancer therapy using a monoclonal antibody (mAb)-photosensitizer (IR700 fluorescence dye) conjugate and exposure of near-infrared light. Although photoimmunotherapy successfully treated EGFR-positive A431 cells in the mixed tumor, EGFR-negative Balb/DsRed cells were not responsive. However, photoimmunotherapy also induced a large increase in tumor permeability, known as the super-enhanced permeability and retention (SUPR) effect, which allowed a 5-fold increase in the accumulation of a liposomal chemotherapy (DaunoXome) and resulted in more effective therapy than either photoimmunotherapy or liposomal daunorubicin alone. The liposomal daunorubicin, administered 1 hour after EGFR-targeted photoimmunotherapy, was homogeneously distributed, allowing delivery to tiny surviving nests of EGFR-negative Balb3T3/DsRed cells, resulting in prolonged survival of mice.