The unrest follows a deadly wave of violence in the metropolis that claimed 85 lives in the wake of the death of lawmaker Raza Haider, who was shot dead by gunmen in August.
The targeted killings come as the city heads to the polls on Sunday to vote in a replacement for Haider, a Muttahida Qaumi Movement (MQM) lawmaker, to a seat in the provincial assembly in the teeming city of 16 million.
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"Twenty-one people have been killed in targeted killings in western and southern neighbourhoods of Karachi since Saturday," city police chief Fayyaz Leghari told AFP.
"At least 17 people were killed Saturday and four more people died Sunday after gunmen opened fire on a passenger bus in Banaras town," Leghari added.
He said the police had arrested 20 suspects during raids and were continuing to investigate.
Tensions are high between MQM and the Awami National Party (ANP), which each represent different communities in Karachi, straddling political fault lines in the city.
Karachi is plagued by ethnic and sectarian killings, crime and kidnappings.
A founding member of MQM, Imran Farooq, who was living in exile in Britain, was brutally murdered outside his north London home in September.
MQM is a partner in the ruling coalition led by the Pakistan People's Party in the southern province of Sindh, of which Karachi is the capital.
The government has not released exact figures, but rights groups say more than 260 targeted killings were reported in Karachi during the first six months of this year, compared with 156 during the same period in 2009.
