Topalov, who played black, beat his American opponent at the 32nd move, building his lead to a comfortable 1.5:0.5.
During the first match on Tuesday, the two finished with a tie.
There are at least six more matches to go, and if their points are even then, Kamsky and Topalov will meet in a tie-break.
According to the schedule, Thursday is a rest day, and the third match will be played on Friday.
Topalov, currently ranked number one in the world, is a former world champion and a fiery competitor. He has been among the world's best players for years, but it was only after the retirement of Garry Kasparov in 2005 that he broke through to the top.
Kamsky, No. 17 in the world, was a prodigy. He rose as high as No. 4 by the time he was 21.
The World Chess Challenge 2009 will continue until February 28 in the National Palace of Culture. The winner will compete for the World title against the current World chess champion Viswanathan Anand of India.
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