Five Palestinians have been killed and more than 500 hurt in clashes with Israeli soldiers along the Israel-Gaza border on Friday, the Palestinian health ministry said.
The ministry said some protesters were hit by live bullets and rubber-coated steel pellets, while others were overcome by tear gas.
A Palestinian farmer was killed earlier in the day by Israeli tank fire in southern Gaza.
The clashes erupted at the start of a planned weeks-long protest along the border that is supported by the Islamic militant group Hamas that rules Gaza.
Friday was being observed as Land Day to mark the anniversary of the killing of six Palestinians by Israeli forces during protests on March 30, 1976 against government plans to seize land for settlement.
Thousands of Gaza residents streamed to five tent encampments, each located about several hundred metres from the border. From there, large crowds marched to the fence, and some among them started throwing stones at soldiers who responded with live fire, tear gas and rubber bullets.
The Israeli military said thousands participated in the clashes, and that troops opened fire at the "main instigators."
The military said it viewed with "great severity any breach of Israeli sovereignty or damage to the security fence".
Israel's military said ahead of the protests that it had doubled its standard troop level along the border, deploying snipers, special forces and paramilitary border police units, which specialise in riot control.
Previous protests near the border fence in recent months have turned deadly, with Israeli soldiers firing live bullets at Palestinians burning tyres, throwing stones or hurling firebombs.
On Friday, mosques across Gaza called on people to join the protests. Buses took protesters to the border area, including the five tent encampments where thousands had arrived by noon.
Hamas spokesman Fawzi Barhoum said the large crowds "reflect the Palestinian people's determination to achieve the right of return and break the siege and no force can stop this right".
Ismail Haniyeh, Hamas' supreme leader along with Gaza leader Yehiyeh Sinwar visited the tents.
The sit-ins are seen as a new attempt by Hamas to break a crippling, decade-old Gaza border blockade by Israel and Egypt that has made it increasingly difficult for the Islamic militant group to govern.
Other tactics over the years, including cross-border wars with Israel and attempts to reconcile with political rival Mahmoud Abbas, the West Bank-based Palestinian president, have failed to end Gaza's isolation.
Friday's actions are to be the first in a series of protests planned in Gaza in the coming weeks. The activities are to culminate on May 15, the 70th anniversary of Israel's creation, with a march through the border fence.
Palestinians commemorate the date as the Nakba, or "catastrophe, marking their mass displacement and uprooting during the 1948 Mideast war over Israel's creation. The vast majority of Gaza residents are descendants of Palestinians who fled or were driven from communities in what is now Israel.
Hamas has fought three wars with Israel since 2008 and Israeli chief of staff Lieutenant General Gadi Eisenkot has warned that the latest protest posed the most serious risk of renewed conflict since he took up his post in 2015.
Several hours before the confrontations, a Palestinian farmer was killed by an Israeli tank shell in the southern Gaza Strip, the Gaza health ministry said.
The ministry identified the farmer killed on Friday as Omar Samour, 27. Witnesses said he was working his land near the border when the shells hit.
The Israeli army said "two suspects approached the security fence along the southern Gaza Strip and began operating suspiciously".
"In response an [Israeli] tank fired towards them," an army spokesman said.
Yasser Samour, a relative of the slain farmer, said Omar was harvesting parsley before dawn, in hopes of selling it fresh in the market later in the day.
"I was working on the next field," Mr Samour said. When he heard shelling landing on the field where Omar worked, "we ran there and found him hit directly with a shell. We were more than a kilometre away from the border."
Another farmer was wounded in the leg by shrapnel, he said.