The ships, led by the 8,030-ton Nisshin Maru, set sail from the southern Japanese port of Shimonoseki.
Officials say the fleet has a target of killing 850 minke whales and 10 fin whales before returning to Japan in April. Minke, a relatively small species, are fairly plentiful in the Antarctic. The larger fin whales are more rare.
Japan began conducting the annual research hunts after the International Whaling Commission or IWC imposed a global ban on commercial whaling in 1986.
Japanese officials claim the program — and the use of lethal harpoons — are needed to gauge whale populations, and to study their breeding and feeding habits.
Marine biologists study the killed whales' bones and stomach contents.
The program is allowed by the IWC, which uses its data and approves its kill quotas, but many environmental groups say the hunts are a pretext to keep Japan's tiny whaling industry alive.
Meat from the catch is sold commercially, and canned or frozen whale can be found in most large supermarkets, though it is no longer an important part of the Japanese diet.
Japanese officials deny that profits are a goal, saying proceeds from the sales go to fund further research. They also note that the IWC rules mandate the whale byproducts from research must not be wasted.
Hideki Moronuki of the whaling division at Japan's Fisheries Agency said that whaling has become politicized, and that criticism of the research program is off-base.
Moronuki also said that roughly half the IWC members at its most recent meeting, held in June, supported the restart of whaling.
"The idea 20 years ago was to temporarily halt commercial whaling because there was a lack of data," he said. "Our goal is the sustainable management of whale resources, based on scientific data."
The program has many vocal opponents.
Australia's Environment Minister Ian Campbell urged Japan to abandon it immediately.
"This is not science — these are commercial numbers of whales," the Australian Associated Press quoted him as saying. "This is a shameless charade, because despite the slaughter of hundreds of whales by Japan, we have yet to see any viable scientific results."
The AAP report said four protest ships, two each from environmental activist groups Greenpeace and Sea Shepherd, are planning to pursue the fleet as they did last summer, when several clashes resulted.
Greenpeace Japan has protested for the Fisheries Agency to stop the annual hunts, but held no demonstrations as the ships left Wednesday, according to spokesman Junichi Sato.
The Japanese government plans to catch 1,070 minke whales in 2006, as well as a total of 170 Bryde's, sei, sperm and fin whales.
Japan has already caught 35 whales this year off the coast of its northern main island of Hokkaido in a 42-day expedition. That catch was well below the 60 allowed under the coastal program, which like the Antarctic hunts is authorized by the IWC.
The small catch was blamed on bad weather.