The Indian began last year's championship with the back-of-the-grid outfit before he was replaced by Red Bull protege Daniel Ricciardo.
But with Australian Ricciardo moving to Toro Rosso for 2012, 35-year-old Karthikeyan - who briefly returned for his home race in India late last season - has taken back his full-time seat.
The news is a blow to Vitantonio Liuzzi, who had acknowledged that a driver with higher-paying sponsors could oust him for 2012 despite his long-term contract.
Karthikeyan will be Pedro de la Rosa's teammate.
"It has taken a lot of hard work to make this happen but I am absolutely elated to feature on the 2012 grid with HRT F1 team," he said in a statement on Friday.
De la Rosa will begin HRT's pre-season preparations at Jerez next week, before Karthikeyan drives at the second test, at Barcelona.
