Civil Defence officials say there could be up to 10,000 casualties when the Alpine Fault ruptures - and 1000 could be fatal.
The West Coast would suffer most of those casualties and Christchurch will be relatively unscathed in comparison.
The figures have been revealed by Civil Defence emergency management group leader James Thompson, as Civil Defence, hospitals, police and other emergency services plan for a major exercise to prepare for The Big One.
The Alpine Fault is expected to rupture within 50 years, a one-in-500 year event that will produce a devastating earthquake of a magnitude 8 or more.
Towns and cities throughout the South Island will feel its tremendous power, with those on the West Coast taking most of its brunt.
Settlements and possibly towns are expected to be cut off for long periods because of landslides and wrecked roading and other links.
The predictions come as Civil Defence and emergency services across the South Island wait for the release of a Canterbury University study into the effects of the Alpine fault quake.
It will form the basis of a major South Island-wide Civil Defence exercise on May 29.
The study is being carried out by Canterbury University geological sciences student, Tom Robinson, who is examining what will happen when the Alpine fault ruptures.
The mock disaster has been called "Exercise Te Ripa Hapa" (loosely translated as "Alpine fault earthquake") and will be activated in Marlborough, Nelson-Tasman, West Coast, Canterbury, Southland and Otago.
Mr Thompson said the force of the quake for Christchurch people would be similar to the 7.1 magnitude September 4, 2010 event.
"It is expected that this would be more of a rolling earthquake which could continue for up to one or two minutes," he said.
Mr Thompson said he would expect serious disruption to roading in Canterbury, including rock falls which would cut off the Arthur's Pass and Lewis Pass with disruption to power and telecommunications.
City council unit manager for Civil Defence Murray Sinclair said he didn't expect building collapses like the February quake in Christchurch, but said unstable rocks on the Port Hills could present a problem.
Mr Thomson said a real rupture of the Alpine Fault was a reality.
"It is always a challenge to do this type of scenario as you don't want to cause alarm bells, but this is a reality. It is a case of not if but when. It is better if we are prepared," he said.