Paolo Di Canio has been cut from 7/4 to 4/5 by Sky Bet to be the first Premier League boss to leave his job this season following Sunderland's 3-0 loss at West Brom.
The defeat left the Black Cats rooted to the foot of the table after five games with a solitary point to their name, prompting the online bookmaker to cut their relegation odds from 7/4 to 6/5.
It was also followed by extraordinary scenes as the Italian boss confronted the disgruntled travelling fans after the final whistle.
Sky Bet Football Trader Chris Spicer said: "We already had Di Canio as favourite to be the first boss to go following a run of bets at the start of the month, but what we saw at The Hawthorns has prompted his odds to be trimmed further.
"Sunderland are now the second favourites to go down, slipping below new boys Cardiff (9/4) and Hull (5/4) in the relegation betting, and with Liverpool and then Manchester United up next it is difficult to see them turning their fortunes around quickly."
Newcastle boss Alan Pardew is the next man in the sack race after a surprise 3-2 defeat against Hull.
The Magpies are 7/1 for the drop, while Fulham are available at 4/1 after losing 2-0 to Chelsea in the Saturday Night Football clash.
The Blues now top the Premier League table and sit just below 12/5 favourites Manchester City in the title betting at 5/2.
Liverpool departed the summit after losing 1-0 at home to Southampton and the Reds are now 12/1 to finish at the head of the table and 6/4 for a top-four spot.
Although Liverpool's defeat was bad news for most football punters, victory for Southampton rounded off one of Sky Bet's enhanced multiples. Saints were grouped with surprise winners Hull plus Everton, who won 3-2 at West Ham, and Aston Villa, who beat Norwich 1-0, in an away-day accumulator which paid a massive 200/1.
Sky Bet's head of football Paul Wiggins said: "An excellent set of results from the 1500 BST games were slightly dampened after a 200/1 enhanced accumulator left some Sky Bet customers enjoying a profitable day as many others suffered."