Several lines of evidence have indicated that the Mentawai segment of the Sumatran megathrust is very likely to rupture within the next few decades. The present study is to investigate seismic hazard and risk levels at major cities in Sumatra, Java, Singapore, and the Malay Peninsula caused by the potential giant earthquakes. Three scenarios are considered. The first one is an Mw 8.6 earthquake rupturing the 280 km segment that has been locked since 1797; in the second scenario, rupture occurs along a 600 km segment covering the combined rupture areas of the 1797 and 1833 historical events, producing an Mw 9.0 earthquake; and the third scenario has the same rupture area as the second scenario but with doubled slip amplitude, resulting in an Mw 9.2 earthquake. Simulation results indicate that ground motions produced by the hypothetical scenarios are strong enough to cause yielding to medium- and high-rise buildings in many major cities in Sumatra. It is vital to ensure that the overall strength, stiffness, and integrity of the structures are maintained throughout the entire duration of shaking. However, the ductile detailing in current practice is formulated based on an assumption that ground motions would last from 20 to 40 sec. This has not been tested for longer durations of 3–5 min, expected from giant earthquakes. In Singapore and Kuala Lumpur, only medium- and high-rise buildings, especially those located on soft-soil sites, are at risk. Given that seismic design has not been required in either city, and thus the resulting structures are relatively brittle, it is crucial to investigate their performance under moderate-amplitude, long-duration, ground motions. The present study also points out that shifting the response spectrum toward a longer period range becomes significant for sites located far from potential seismic sources, which should be carefully considered in formulation of future seismic codes.