World Cup winners Ben Cohen and Steve Thompson will miss England's two-Test tour of Australia this summer.
Northampton wing Cohen and Saints hooker Thompson have both opted to rest in preparation for next season.
The pair, who boast exactly 100 caps between them, are set to join a prominent list of absentees Down Under when England face Australia in Sydney on June 10 and Melbourne a week later.
Wasps back Josh Lewsey and his club colleague, lock Simon Shaw, could also miss the trip, with England captain Martin Corry another possible non-starter as head coach Andy Robinson identifies those players requiring essential rest and recuperation.
Northampton centre Jon Clarke, meanwhile, is remaining at home to undergo a hernia operation that will require eight weeks' rehabilitation.
Clarke, who represented England A this term, would have been a strong midfield contender for the Australia trip.
"The injury has been troubling me on and off, and I just don't want it to worry me next season," he said. "I should be back fresh for pre-season."
Elsewhere, Saints say hooker Dylan Hartley will not be considered for England's Under-21 World Cup campaign in France next month due to a back injury that is currently being assessed by a consultant.
Saracens director of rugby Mark McCall believes Alex Lozowski has only just scratched the surface of his potential after the 23-year-old celebrated his England recognition by scoring a try-double against Bristol.