The strike, the fifteenth since April, is set to disrupt services into Johannesburg and Cape Town.
Weekend talks failed to bring the two sides to an agreement.
The German pilots’ union said the walkout would affect Lufthansa’s short-haul flights on Tuesday, and both short and long-haul flights on Wednesday.
The airline cancelled nearly 2,800 flights last week due to a four-day walkout by pilots and the company estimates the action is costing it R160 million a day.