Two school classes are self-isolating after two days of term because a teaching assistant has coronavirus.
The member of staff at Cardinal Newman school in Hove was contacted by track and trace on Thursday and told on Friday they had tested positive.
Principal Claire Jarman alerted parents on Friday and 45 pupils in two Year 7 classes were affected by the news.
Chairman of governors Geri Silverstone said the school was doing all it could to keep pupils and staff safe.
Four year groups returned to school last week, with the whole cohort due back on Monday.
Ms Jarman wrote to parents: "We fully appreciate this is not the start to the new term any of us would have wished for."
Five members of the learning support team are also self-isolating.
Mr Silverstone said the school immediately alerted Brighton Council, Public Health England and unions.
He said: "We are reassuring students when they return on Monday that it will be a very different experience but it will be as safe as we can make it."
Cardinal Newman, one of the largest schools in the south-east of England, is a voluntary-aided secondary school with about 2,500 pupils.
A council spokesman said: "We are closely monitoring the situation... and are urging everyone to follow public health guidance to stop the spread of infection."
Kevin Courtney, general secretary of the National Education Union, said it supported the return to schools but called for more teachers, additional space, a more robust track and trace system and testing centres within a reasonable distance.
He added: "Despite the inconvenience and disruption caused it is inevitable that cases in schools will lead to some children and staff having to self-isolate."
A spokesman for the Department for Education said: "We have a clear published process for what happens when someone who tests positive is known to have been in school.
"If a positive case is confirmed, swift action will be taken to ask those who have been in close contact with them to self-isolate, and Public Health England's local health protections teams are standing ready to support and advise schools in this situation.
"Children who are self-isolating will continue to receive remote education from home."
He said laptops were being provided to disadvantaged children and measures were in place to keep people safe.