The three policemen were killed and their colleague was injured when they were on patrol duty last night in the suburbs of Latifabad township.
The injured was rushed to a hospital.
"Masked men on motorcycles opened indiscriminate firing on the police mobile killing three of them on the spot while another has been critically injured," DIG Sanaullah Abbasi said.
"These killings of could be a retaliation to the ongoing operation against terrorists in North Waziristan," Abbasi told reporters in Hyderabad after visiting the injured policemen in hospital.
In Karachi, around 91 cops this year have perished in the targeted killings.
The killings in Hyderabad came hours after the Muttahida Qaumi Movement, single largest party in the region, held a massive rally in front of the Quaid-e-Azam mausoleum in Karachi to express solidarity with the the army and its operation against militants in North Waziristan.
The paramilitary Rangers had Saturday shot dead two suspected Tehreek-e-Taliban militants in Karachi.
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