Around 3.8m people who are on England's shielding list will start receiving letters from today setting out updated advice, the DHSC said.
The new guidance recommends that clinically extremely vulnerable people continue to take additional precautions after 1 April, such as working from home and following social distancing measures.
People who are unable to work from home have been advised that they can attend work from 1 April. However the letter also advises people to minimise the number of social interactions they have and follow advice relating to ventilation when rules change to allow meeting people indoors.
More than nine in 10 clinically extremely vulnerable patients have received a first dose of the COVID-19 vaccine. However the government said it was still important that these people followed the additional precautions 'to keep themselves as protected as possible'.
Local authorities will continue to provide support for those on the shielded list until 31 March and individuals will be able to access priority supermarket delivery slots until 21 June if they have already registered for these.
GPs have been asked to continue to maintain the shielding list in case it is necessary to identify clinically extremely vulnerable people in the future and shielding needs to be reintroduced.
The decision to relax the advice around shielding comes as the number of cases of COVID-19 continues to fall.
Deputy CMO for England Dr Jenny Harries said: 'Shielding has always been an advisory measure to safeguard those who are the most clinically vulnerable in our communities. We recognise how difficult this period has been for so many and the impact it has had on people’s wellbeing.
'With the prevalence of the virus in the community continuing to decrease now is the right time for people to start thinking about easing up on these more rigid guidelines.
'If you have been shielding, we strongly urge you to take extra precautions following 1 April to keep yourself as safe as possible, such as continuing to observe social distancing and working from home. We will continue to monitor all of the evidence and adjust this advice should there be any changes in infection rates.'
Shielding was reintroduced when England went into lockdown at the start of January this year, although people living in what were classed as tier 4 areas had been advised to shield before Christmas.
Last month an additional 1.7m people were added to the shielding list based on data from the QCovid risk assessment tool. The model, developed by the University of Oxford, identifies people at greater risk from COVID-19 due to their individual circumstances and is based on data from their health records.