Klitschko won the title in 2004 but "retired" later that year through injury only to resume his untroubled reign four years later.
Klitschko, who is based in Germany, improved his record to 44 wins and two losses with his 41st stoppage while Zimbabwe-born Chisora, who moved to London aged 16, suffered his third defeat in his 18th fight.
Chisora, 28, had lost his previous fight - controversially on points to Finland's Robert Helenius for the European title in December - but his aggressive start showed the Briton had strong intentions for Klitschko and was not intimidated, unlike a lot of Vitali's previous challengers.
Chisora marched forward in the second round but was caught by a right on the temple before landing a short right hook of his own.
Many of Klitschko's fights have been one-sided but Chisora made the early rounds competitive.
Klitschko, 15cm taller, began having success with the right over the top but it did not discourage Chisora from walking on to the champion.
Klitschko refused to let his hands go, no matter how provoked he had been, and built up a comfortable points lead by the halfway mark.
Klitschko declared that after fighting Chisora he would have one more fight before considering hanging up the gloves.
- AAP