Aman Tuleyev, the longtime governor of Russia's Kemerovo region where a huge mall fire killed at least 64 people including 41 children last weekend, resigned on Sunday.
Tuleyev, who had been at the helm of the key coal-mining region since 1997, said in a video address that he could no longer remain at his post with "such a heavy burden" and added that his resignation was "the only right choice."
President Vladimir Putin accepted his resignation, the Kremlin said.
The fire ravaged a mall in the industrial city of Kemerovo in western Siberia last Sunday, a tragedy that plunged Russia into shock.
Some parents lost all their children, and the youngest victim was a two-year-old toddler.
Many people who lost relatives have said they died because of the inaction of firefighters and police lacking the necessary equipment and skills.
Tuleyev himself came under heavy criticism for failing to visit the scene of the tragedy in the first few days or meet with angry relatives.
Putin - who travelled to Kemerovo last Tuesday - had initially refused to sack the 73-year-old governor despite rare protests in the city.
Tuleyev apologized to the president over the rally calling its organizers troublemakers.
Officials have said that multiple safety rules were violated, the fire alarm system was not working and staff did not follow correct emergency procedures.
Sergei Tsivilyov, who has been Tuleyev's deputy since March, has been appointed acting governor, the Kremlin said.
The ailing Tuleyev had long been expected to leave the post.
The coal-mining Kemerovo region of around 2.7 million people has traditionally been considered one of Russia's most troubled regions and some have feared that Tuleyev's departure could spark a leadership crisis there.
Tuleyev, who first became governor in the era of President Boris Yeltsin in 1997, is one of Russia's longest-serving top officials.
He was credited with helping pacify the region which was beset by miners' strikes in the turbulent 1990s but had come to symbolize the worst excesses of authoritarianism in his later years, critics say.
Polls to elect a new governor will be held in September.
"This tragedy reflects all of Russia's problems - the corruption of officials who closed their eyes to problems with fire safety, uncoordinated work of the special services, the imperviousness of authorities," said Rasim Yaraliyev, head of a citizen's group pressing for answers about the fire.
Six people have been arrested in the case, including the head of the regional construction inspection agency when the shopping center was developed in a former candy factory, and the general director of the company that owns the mall.