Dubbed the Blade Runner for the two carbon fibre prosthetic blades he uses, Pistorius finished half a second ahead of his nearest rival in the T43 heats winning in 21.3 seconds.
His run marked the start of his quest to retain his three Paralympic sprint titles.
The 25-year-old, also known as "the fastest man on no legs", has become the face of the Paralympics.
He said: "I just wanted to have a good race. I am so happy to be back here, this crowd is as awesome as they were a couple of weeks ago.
"I am happy with the time but tomorrow is the big race [the final] and I am looking forward to it."