Ship damage caused by maritime casualties leads to marine pollution and loss of life and property. To prevent serious damage from maritime casualties, several types of safety regulations are applied in ship design. Damage stability regulation is one of the most important safety issues. Designs of ships for long international voyages must comply with these regulations. Current regulations, however, do not consider the characteristics of the operating route of each ship and reflect only ship size and type of cargo. In this paper, a damage safety assessment was undertaken for a ship carrying radioactive waste in actual wave conditions. Damage cases for safety assessment were constructed on the basis of safety regulations and related research results. Hull form, internal arrangement, loading condition and damage condition were modeled for damage safety simulation. The safety simulation was performed and analyzed for 10 damage cases with various wave heights, frequency and angle of attack on an operating route. Based on evaluation results, a design alternative was generated, and it was also simulated. These results confirmed that damage safety analysis is highly important in the design stage in consideration of the operating route characteristics by simulation. Thus a ship designer can improve safety from damage in this manner.