A first-half goal from Enrique Vera and a late strike from Cristian Riveros at Free State stadium gave Paraguay the crucial win that takes them to four points with only Group F minnows New Zealand still to play.
Paraguay took the lead on 27 minutes when Vera bent the ball around the goalkeeper with the outside of his right boot after a pass from Lucas Barrios.
After a more even start to the second half, the South Americans once again established a grip on the match as Slovakia struggled to break down their defence.
The World Cup hopes of Slovakia now hang by a thread with Italy still to play.
Italy, who drew 1-1 with Paraguay in their opener, were playing New Zealand in Nelspruit in the later kick-off.
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