A 12-year-old girl is believed to have taken a gun into school and shot a 15-year-old boy in the head.
Television footage has shown police leading a girl away from the school in Los Angeles after they were called to reports of gunshots in a classroom shortly before 9am.
The boy was taken to hospital and is said to be in a critical but stable condition. A gun has been recovered from the scene.
Emergency services have launched an investigation into the shooting at Salvador B Castro Middle School, close to LA's downtown area, but no motive has been established.
The girl, who has not been named, has been taken to hospital after she was shot in the wrist.
Three other people, ranging in age from 11 to 30, were treated for minor cuts and scrapes after the shooting.
Los Angeles police kept parents updated on Twitter and in a meeting outside the school, saying if they had not heard from their child, they were safe and well.
Steve Zipperman, chief of the Los Angeles Unified School District police force said: "We will attend to the needs of these students who witnessed this very carefully, with the understanding this is very traumatic.
"We have our school mental health folks that are here to support the needs of the students."
The district has a policy which states random searches should be carried out daily with a metal detector wand. It is not yet clear if one of those had happened yet on Thursday.
Interim Superintendent Vivian Ekchian of the LA Unified School District, said: "Our thoughts and prayers are with those who were hurt in today's shooting incident at Sal Castro Middle School and with all the students, families and employees on the campus.
"The Los Angeles Police Department, Los Angeles Fire Department, Los Angeles School Police and District leadership immediately responded, and we followed protocols to ensure the safety and well-being of the Castro Middle School community.
"The school has been declared safe, and we are communicating with parents of students at Castro Middle School, as well as neighbouring campuses.
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"We are fully co-operating with the Los Angeles Police Department in its investigation of this matter."
The school shares a campus with Belmont High School.