In the last 32 Higgins, who missed the recent German Masters, will face 19-year-old Jack Lisowski, who is in his first season on the professional tour.
Jimmy White faces Ryan Day for a last-32 meeting with Ronnie O'Sullivan.
Masters finalist Marco Fu beat Joe Swail and plays world number two Mark Williams, who won the German title.
Another Welshman, Dominic Dale, defeated Mark Davis 4-2 to secure a meeting with the obdurate Peter Ebdon.
This year's event sees a best-of-seven frame format with no intervals up to the last 16 stage.
Lisowski, from Churchdown, Gloucestershire, beat Liam Highfield 4-1 and Fergal O'Brien 4-0 earlier in the week, before runs of 72, 59, 100 and 62 helped him to a 4-3 win over Martin Gould.
"I wanted to win, not for the prize money or ranking points, but so that I'd have the chance to play John Higgins on a big stage," Lisowski said.
"It will be a great chance to learn, and that's my attitude in all of these matches, they are all about learning how to improve my game. I've definitely exceeded my expectations this season, although I felt that I could win a lot of matches."
Lisowski, who himself overcame Hodgkin's Lymphoma in 2009, added: "I'm sure it will be difficult for John.
"I met his dad at the Crucible when I was a kid. He was really nice and took the time to talk to me. It's really sad that he's gone now."
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FIRST ROUND Draw(best of 7 frames)
Mon 1400: John Higgins (Sco) v Jack Lisowski (Eng)
Mon 1100: Ricky Walden (Eng)v Dave Harold (Eng)
Wed 1900: Ronnie O'Sullivan (Eng) v Ryan Day (Wal)/Jimmy White (Eng)*
Wed 1300: Shaun Murphy (Eng) v Matthew Stevens (Wal)/Anthony Hamilton (Eng)**
Mon 1300: Ali Carter (Eng) v Barry Hawkins (Eng)
Tue 1400: Peter Ebdon (Eng) v Dominic Dale (Wal)
Tue 1300: Mark Allen (NI) v Rod Lawler (Eng)
Mon 1100: Ding Junhui (Chn) v Marcus Campbell (Sco)
Tue 1300: Mark Williams (Wal) v Marco Fu (HK)
Mon 1900: Jamie Cope (Eng) v Rory McLeod (Eng)
Wed 1300: Stephen Hendry (Sco) v Joe Perry (Eng)
Wed 1400: Stephen Maguire (Sco) v Gerard Greene (NI)
Tue 1400: Mark Selby (Eng) v Stuart Bingham (Eng)
Mon 1400: Mark King (Eng) v Michael Holt (Eng)
Tue 1900: Graeme Dott (Sco) v Jamie Burnett (Sco)
Tue 1900: Neil Robertson (Aus) v Nigel Bond (Eng)
* Day v White - Mon 1900
** Stevens v Hamilton - Mon 1100