Three Championship games on 26 December and 10 more in the EFL have been called off because of Covid-19 cases.
Cardiff City v Coventry City, Stoke City-Barnsley and Peterborough-Reading have been postponed in the second tier.
Five games in League One and six in League Two have also been called off.
The English Football League says "there is optimism that disruption can be minimised" and confirmed that league, Carabao Cup and Papa John's Trophy ties can continue "where safe to do so".
League Two leaders Forest Green, who have now suffered three successive postponements,
head the list of six games called off so far in the fourth tier.
Their trip to Newport is off, as is Bristol Rovers v Sutton United, Northampton Town v Walsall, Bradford City v Harrogate, Stevenage v Crawley Town and Exeter City v Swindon Town.
The League One match between Bolton and Morecambe became the first in the division to be called off on Tuesday - with the Trotters since suspending training until 27 December as 14 players, and manager Ian Evatt, have tested positive for coronavirus - while Portsmouth against Oxford United is also off.
Sheffield Wednesday against Burton Albion, Wycombe versus Cambridge United and Gillingham against Ipswich were all postponed on Wednesday.
Following the introduction at clubs of daily lateral flow tests for all first-team players and staff, more fixtures are likely to be postponed as national figures rise following the effect of the Omicron variant.
"Throughout the pandemic, our two priorities have been ensuring the welfare of those involved in EFL competitions and ensuring the fixture schedule can continue where it is safe to do so," said EFL chief executive Trevor Birch.
"We will continue to work with clubs, authorities and other agencies to monitor the Covid-19 case rate and be prepared to respond accordingly. Yet, for now, the view remains that we can continue to deliver games safely where clubs have sufficient healthy personnel in place, on and off the pitch.
"With club mitigation measures, the mass adoption of booster jabs and Covid certification now required for larger crowds, we are sure many fans will continue to feel confident in attending matches over the Christmas period and we look forward to welcoming them."
Championship
Barnsley v Stoke City
Cardiff City v Coventry City
Peterborough United v Reading
League One
Bolton v Morecambe
Gillingham v Ipswich
Portsmouth v Oxford United
Sheffield Wednesday v Burton Albion
Wycombe Wanderers v Cambridge United
League Two
Bristol Rovers v Sutton United
Bradford City v Harrogate Town
Exeter City v Swindon Town
Newport County v Forest Green Rovers
Northampton Town v Walsall
Stevenage v Crawley Town
National League
Barnet v Boreham Wood
FC Halifax Town v Grimsby Town