Some fatal accidents occurred to vessels in loading conditions characterized by large metacentric height indicate that such loading conditions could lead to problems from a safety perspective. The issue has been addressed in the framework of International Maritime Organization (IMO) Second Generation Intact Stability Criteria (SGISC) by introducing “excessive accelerations” as a specific failure mode. However, safety-oriented studies in this respect are still not numerous, and further data for IMO SGISC development are also needed. Therefore, this paper addresses the behavior at sea of a container vessel from a safety perspective, using nonlinear time domain ship motion simulations. Two loading conditions are considered, where one of the two is characterized by a relatively large metacentric height. Human-related and systems&machinery-related hazards, which are linked to ship motions through appropriate failure conditions, are taken into account. Short-term and long-term safety level indicators determined for the two considered loading conditions are compared and discussed.