The prime minister “strongly condemns” a five-day strike disrupting services for hundreds of thousands of Southern passengers, Downing Street has said.
Hundreds of trains have been cancelled in a row over plans for drivers, not conductors, to operate carriage doors.
The RMT union claimed “rock-solid support” and said the central issue was safety.
A spokesman for Theresa May said the action was “only going to cause more disruption and misery”.
946 trains cancelled
Southern said it was operating nearly 60% of its regular timetable and nine in 10 of those were “running on time”.
A spokeswoman admitted 946 of its normal 2,242 services would be cancelled each day during the stoppage.
Parent rail firm Govia Thameslink (GTR) thanked passengers for their “patience and understanding” and called on the RMT “to let this strike be the last”.
BBC Correspondent Ben Thompson said the strike, which started at 00:01 and ends at 23:59 BST on Friday, is the longest on the railways since 1968.
The RMT has held a series of one-day strikes since April after balloting 393 members.