The Jumbo-Visma and Mitchelton-Scott teams have withdrawn from the Giro d'Italia after six positive results in the latest round of Covid-19 testing.
General classification contender Steven Kruijswijk, who rides for Jumbo, tested positive as did four staff members of the Australian Mitchelton-Scott team.
Out of 571 tests, Team Sunweb's Michael Matthews also tested positive.
Mitchelton-Scott's British rider Simon Yates, another pre-race favourite, tested positive before stage eight.
"As a social responsibility we've made the decision to withdraw," said Mitchelton-Scott boss Brent Copeland.
Kruijswijk, ruled out of last month's Tour de France because of a shoulder injury, said: "Within the team we take a lot of measures to avoid contamination.
"And I just feel fit. I can't believe I got it. It is a very big disappointment to get this news. It is a pity that I have to leave the Giro this way."
In a statement on their website, Team Sunweb said: "Michael is currently asymptomatic, feels healthy and is now in quarantine."
A staff member from Team AG2R-La Mondiale and Team Ineos Grenadiers also tested positive and are now isolating.
The latest rounds of tests were carried out on 11 and 12 October.
In Tuesday's 10th stage, three-time world road champion Peter Sagan won the undulating 177km run from Lanciano to Tortoreto on the Adriatic coast.
It was an eventful stage in which Slovakian Sagan survived from the early breakaway and stayed out in front, fighting his way up steep climbs in heavy rain - as well as negotiating slippery descents on new tarmac.
There were moves in the general classification contenders, where Domenico Pozzovivo of NTT and Jakob Fuglsang of Astana suffered punctures - the latter losing more than a minute.
Deceuninck-Quick Step's Joao Almeida held on to the pink jersey, extending his lead to 34 seconds - with four bonus seconds for finishing third - over Wilco Kelderman of Sunweb.
The Grand Tour race, originally scheduled for May, finishes on 25 October.
Matt Warwick, BBC Sport cycling reporter
The Giro d'Italia appears to be unravelling before our very eyes, to what could be a premature ending.
There are nearly two weeks remaining of this delayed Grand Tour, but the first rest day of coronavirus testing proves Covid 19 is now in the race 'bubble'.
Following a relatively successful Tour de France, in which no riders were directly affected, Giro organisers RCS introduced the same model: pre-race testing and further tests on the two rest days.
They, and cycling's governing body the UCI, must now consider at what point they would have to end the race early if more riders, or whole teams, pull out.
The loss of Kruijswijk blows the race further open, as he is the third of the favourites for victory to abandon after Simon Yates tested positive and Geraint Thomas of Ineos Grenadiers pulled out with an injury.
The ever colder Italian Alps await an unpredictable conclusion - if the race gets there at all.
Stage 10 result
1. Peter Sagan (Svk/Bora-Hansgrohe) 4hrs 1min 56secs
2. Brandon McNulty (US/UAE-Team Emirates) +19secs
3. Joao Almeida (Por/Deceuninck-Quick-Step) +23secs
4. Ben Swift (GB/Ineos Grenadiers) same time
5. Jai Hindley (Aus/Sunweb)
6. Rafal Majka (Pol/Bora-Hansgrohe)
7. Patrick Konrad (Aut/Bora-Hansgrohe)
8. Wilco Kelderman (Ned/Sunweb)
9. Domenico Pozzovivo (Ita/NTT Pro Cycling Team)
10. Pello Bilbao (Spa/Bahrain-McLaren)
1. Joao Almeida (Por/Deceuninck-Quick-Step) 39hrs 38mins 5secs
2. Wilco Kelderman (Ned/Sunweb) +34secs
3. Pello Bilbao (Spa/Bahrain-McLaren) +43secs
4. Domenico Pozzovivo (Ita/NTT Pro Cycling Team) +57secs
5. Vincenzo Nibali (Ita/Trek-Segafredo) +1min 1sec
6. Patrick Konrad (Aut/Bora-Hansgrohe) +1min 15secs
7. Jai Hindley (Aus/Team Sunweb) +1min 19secs
8. Rafal Majka (Pol/Bora-Hansgrohe) +1min 21secs
9. Fausto Masnada (Ita/Deceuninck-Quick-Step) +1min 36secs
10. Hermann Pernsteiner (Aut/Bahrain-McLaren) +1min 52secs
14. Tao Geoghegan Hart (GB/Ineos Grenadiers) +2mins 45secs
18. James Knox (GB/Deceuninck-Quick Step) +5mins 32secs