Orkambi is only indicated for these patients, who can be identified with a genetic test.
The company said that Orkambi will be available for shipment to specialty pharmacies in the US within days.
The approval was based on data from two Phase III trials (Traffic and Transport) that enrolled more than 1,100 people with CF aged 12 years and older with two copies of the F508del mutation.
Vertex chairman, president and chief executive officer Jeffrey Leiden said: "More than 15 years ago, our scientists set out to discover and develop medicines to treat the underlying cause of cystic fibrosis.
"Today, the approval of Orkambi represents a fundamental change in the treatment of the most common form of CF, marking significant progress for us and for the entire CF community.
"While we celebrate this important step forward, we also recognize that two out of three patients in the US still do not have a medicine to treat the underlying cause of their disease."
In the trial, patients treated with Orkambi experienced statistically significant improvements in lung function as well as reductions in pulmonary exacerbations and improvements in body mass index (BMI).