Penrith will rest the majority of their State of Origin stars with only Liam Martin a chance to back-up and play two days after the series opener.
The Panthers confirmed that Nathan Cleary, Jarome Luai, Isaah Yeo, Brian To'o and Kurt Capewell would miss Friday night's clash with Cronulla, as the club opted to take the long game on their stars' fitness.
But Api Koroisau, the 18th man for NSW, will return to the all-conquering Panthers line-up.
Nathan Cleary's fitness was arguably the easiest call for the Panthers, with the halfback nursing five stitches in his face following friendly fire from Tom Trbojevic.
Scans have since confirmed there is no bone damage for Cleary, and despite nursing a black eye he is expected to be fit to face Sydney Roosters next week.
"It's obviously swollen and swelling up this morning but it feels fine," Cleary said on Thursday morning.
Penrith backrower Capewell had earlier told coach Ivan Cleary he was desperate to face his former club Cronulla as the only Panther to feel the pain of a loss on Wednesday night.
Yeo got through 80 minutes at lock in his first start in Origin, while second-rower Martin only played 30 minutes for NSW.
Winger Brian To'o was looking sore at Blues camp after totalling 225 metres and scoring two tries on Origin debut.
Koroisau meanwhile had a far lighter workload as he was not called upon as 18th man.
It means the Panthers will have Tyrone May and Matt Burton partner each other in the halves, while the rest of their backline is still virtually at full strength, with the exception of To'o.
Penrith did have their 12-match winning streak stopped last week without their Origin players, but it's expected the club will take the option of resting players through the Origin period.
"If you're going to have Origin players you need to learn how to live without them as well. Last week was a good lesson for us," coach Cleary said.
It came as several teams faced crucial decisions on Thursday and Friday, as they weigh up short-term success with their stars' long-term fitness.
Tom Trbojevic (rested) and Kyle Feldt (glute) became the first players ruled out on Thursday, with both to miss Friday's Manly-North Queensland clash.
Daly Cherry-Evans and Jake Trbojevic will play for the Sea Eagles, while Valentine Holmes travelled with the Cowboys on Thursday to play.
Other clubs have longer windows to make decisions, although Roosters coach Trent Robinson indicated captain James Tedesco would face Gold Coast on Saturday.
Titans prop Moeaki Fotuaika will however miss that game after pleading guilty to dangerous contact from Origin I and copping a one-game ban.
Christian Welch is also unlikely to run out for Melbourne against the Warriors on Sunday after suffering a concussion early in the Origin game.