This paper examines a practical tactical liner ship route schedule design problem, which is the determination of the arrival and departure time at each port of call on the ship route. When designing the schedule, the availability of each port in a week, i.e., port time window, is incorporated. As a result, the designed schedule can be applied in practice without or with only minimum revisions. This problem is formulated as a mixed-integer nonlinear nonconvex optimization model. In view of the problem structure, an efficient holistic solution approach is proposed to obtain global optimal solution. The proposed solution method is applied to a trans-Atlantic ship route. The results demonstrate that the port time windows, port handling efficiency, bunker price and unit inventory cost all affect the total cost of a ship route, the optimal number of ships to deploy, and the optimal schedule.