Smestow School sent home students in Years 10 and 11 today due to a "positive transmission" from outside the school, its governing body said.
In addition, the school has already closed to Year 8 pupils and sixth form students in Years 12 and 13 due to previous Covid-19 cases. These were also transmitted from outside the school.
At present, only pupils in Years 7 and 9 are being taught inside the grounds.
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However, self-isolating pupils are being taught remotely at home through online learning support.
Professor Michelle Shaw, director of education and CEO of University of Wolverhampton Multi-Academy Trust, said: "Following guidance from the Department for Education [DfE] on school closures during Covid, Smestow Academy has been advised to close to Years 10 and 11 from today.
"Year 8 and VI Form students have been previously closed following government guidance. Currently the Academy is open to Years 7 and 9. All of the Covid infections that have led to closure have occurred as a result of transmission outside of the Academy.
"All students are continuing their education whilst self-isolating through school provided online learning as per DfE guidance and we are providing ongoing support for students and parents where necessary."