According to SAPA, Mtawarira sustained a calf injury which will see him miss at least four weeks of action. On-loan Lions outside back Andries Coetzee also went off with a suspected dislocated shoulder.
Coach John Plumtree said the injuries were not ideal ahead of their departure for their four-leg away tour to New Zealand and Australia.
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"It’s not looking good for Beast and he won’t be on the plane. He’s probably out for four weeks," Plumtree said.
"I was really disappointed about Andries, because I thought he played really well too. He could be out for a couple of months."
Replacements for the injured duo are yet to be named.
The Sharks face the defending champion Chiefs on Saturday (09:35 SA time), followed by matches against the Highlanders, Reds and the Force.
Sharks touring squad (minus Mtawarira and Coetzee):
Forwards:
Anton Bresler, Craig Burden, Marcell Coetzee, Kyle Cooper, Keegan Daniel (captain), Allan Dell, Jean Deysel, Jannie du Plessis, Pieter-Steph du Toit, Derick Minnie, Wiehahn Herbst, Lubabalo Mtembu, Franco van der Merwe
Backs:
Meyer Bosman, Paul Jordaan, Patrick Lambie, Piet Lindeque, Charl McLeod, Odwa Ndungane, JP Pietersen, Cobus Reinach, Sean Robinson, Francois Steyn, Riaan Viljoen