Zaki, 40, was having dinner last night with his friend Rao Khalid at a restaurant when four armed assailants came on two motorcycles and sprayed bullets. Both Zaki and Khalid were rushed to a hospital where they succumbed to their injuries. A bystander named Aslam was also injured in the firing.
The Hakimullah Mehsud faction of the Taliban claimed responsibility for the attack in a statement to the media.
Police, however, said it could not confirm the claim by the Taliban faction.
A senior police investigator said it was more likely a case of target killing and a sectarian attack as both men killed belonged to the Shia community.
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Zaki, a social media campaigner, civil society activist, blogger, journalist and religious scholar, was known for his strong views on the Lal Masjid cleric and led a campaign against him for his extremist views since last year.
Zaki had condemned extremism in all forms and came into limelight when he led the campaign against Aziz for inciting hatred against Shia Muslims.
Zaki also gained fame when he launched a Facebook page "Let Us Build Pakistan" (LUBP) and became editor of a website devoted to working for human rights and spreading liberal religious views.
The page was recently blocked by the Pakistan Telecommunication Authority.
Following Zaki's murder, Sindh Home Minister Sohail Anwar Sial ordered a probe and sought report from police within 48 hours.
Meanwhile, protesters carried the body of Zaki to the Chief Minister's House and staged a protest.
Majlis Wahdat-e-Muslimeen (MWM) has also announced to stage a protest demonstration outside the Chief Minister's House.
"For the last one year, Khurram Zaki was a target of a systematic hate campaign organised by Deobandi fanatic, Shamsuddin Amjad of the Jamaat-e-Islami Pakistan in collaboration with the banned Sipah-e-Sahaba Pakistan," Ali Abbas Taj, LUBP's Editor-in-Chief, said in a statement.