The same fractionation scheme of accelerated partial breast irradiation (APBI) with brachytherapy is usually applied to APBI patients without considering the radiaton effect on the planning target and organs at risk (OARs) for an individual patient. The purpose of this study is to report the results of optimization of the fractionation scheme by evaluating the radiation effect on target and OARs with a modified linear-quadratic model, universal survival curve (USC), based on dose-volume histograms (DVHs). Ten breast patients treated with multilumen balloon brachytherapy were selected. The minimum skin and chest wall/rib (CW/rib) spacing ranged from 2.5 to 14.3 mm and from 0.5 to 25.0 mm, respectively. The USC model parameters were set as: (1) breast:α = 0.3, β = 0.05; (2) skin: acute reaction α = 0.101, β = 0.009; late reaction α = 0.064, β = 0.029; (3) CW/rib: α = 0.3, β = 0.12. Boundary dose Dt was 6 Gy for both target and OARs. The relation between radiation effects on the target (ET) and OARs (EOAR) were plotted for fraction numbers (N) from 1 to 20. If ET is set at a certain value, the fractionation that results in a minimum EOAR value corresponds to the optimal fractionation. The results show that the optimal fractionation is different for different OAR damage effects. For most of the patients, N = 2 is best for minimizing skin acute reactions while N = 20 is best for minimizing skin late reactions. N varies from 3 to 20 among patients for minimizing CW/rib toxicity. The determined unique optimal N for treatment delivery was found to vary from 1 to 20 among these 10 patients resulted from balancing the different damage effects considering the spatial dose for a given patient geometry. Optimal fractionation can be achieved for an individual patient by evaluating the radiation effect on tumor and OARs with the USC model based on the patient specific DVHs with APBI brachytherapy.