Reading's Sky Bet Championship match at home to Luton on Saturday has been postponed due to a Covid-19 outbreak, along with Millwall's game against Preston.
After QPR's visit to Swansea was also postponed, Reading said there had been a 'significant number' of positive PCR tests among both the first-team squad and under-23s.
A statement on the Reading website said: 'The club informed the EFL this morning that, following the return of a significant number of positive PCR tests within our first team and under-23 squads, we are unable to field a team capable of fulfilling the fixture on Saturday.
'In light of the increased rate of transmissions from the Omicron variant of Covid-19, the EFL will review the circumstances surrounding the postponement and work with affected clubs to assist them throughout this challenging period.
'A rearranged date for the fixture will be announced in due course.'
Later on Wednesday, Millwall announced the visit of Preston had also been postponed because of 'a significant number' of positive Covid cases within the playing squad and support staff.
The club statement added: 'At present, only a minority of those who have returned positive test results are experiencing any sort of symptoms and they are very mild at worst.
'The decision to postpone has been made following extensive dialogue with the EFL, Public Health England and the club's safety advisory group.'
Following the announcement, the EFL said it would 'review the circumstances surrounding the postponement and work with affected clubs to assist them throughout this challenging period'.
A rearranged date for the game will be confirmed in due course.
Around the same time on Wednesday, the Premier League postponed Burnley's game against Watford - which was due to kick-off later that evening - after a Covid-19 outbreak in the visiting team.
Earlier on Wednesday, Leicester City said they had a request to postpone Thursday's game against Tottenham Hotspur rejected by the league, as English football continues to face potential disruption from the spread of Covid and the Omicron variant.
The decision to call off the match at Turf Moor came just two-and-a-half hours before the scheduled kick-off time.
'The decision was taken following guidance from medical advisers due to an ongoing Covid-19 outbreak within Watford's squad. As a result, the club has an insufficient number of First Team players available to fulfil the match,' the Premier League said in a statement.
The Premier League's rules state that if a team cannot raise 14 players then a game can be postponed although other factors, such as impact on preparation and whether or not there has been an 'uncontrollable outbreak' are also taken into account.
'In considering any application to postpone, the Board considers a range of sporting and medical factors. Each decision is taken on a case-by-case basis with everyone's health of utmost importance,' the league added.
Manchester United's scheduled game at Brentford on Tuesday was postponed after United closed their training ground due to COVID cases.
