Shock figures show more than 1,700 people on average die every year in Sheffield due to smoking related illness.
Latest statistics from NHS Digital show 298 people per 100,000 of the city population lost their lives to tobacco-related conditions.
But Sheffield stands better than other big towns and cities ranking 21st out of 24 for smoking-related fatalities.
Manchester comes out on top with 509 deaths per 100,000 of the population and Yorkshire neighbours Leeds had 345.
Only York, London and Bournemouth sit below Sheffield in the 24 biggest towns and cities in UK for smoking deaths.
Sheffield Council's top health boss has urged people to ditch traditional tobacco products and switch to an e-cigarette if people were struggling to quit altogether.
Greg Fell, director of public Health, said: “Smoking is still the biggest killer, the biggest burden to public health and a major cause of health inequalities.
“Reducing smoking levels in line with other world leaders in this area is a big priority for me. It’s something we’re working hard on and includes working with schools and young people, introducing more smoke-free areas and running mass-media campaigns.
“There is help for anyone who wants to stop smoking in Sheffield, so please get in touch if you want support. We recommend switching to an e-cigarette if you’re not able to quit, as it’s less harmful to health, but obviously the best thing is to stop smoking altogether.”
Charles Bloom, managing director of Vapourlites.com, who compiled the data, said: “Many people unfortunately become fixated to the addictive nature of smoking and changing this behaviour can be difficult.
"But with more safer alternatives to smoking than ever before and ground-breaking studies/research thoroughly exhibiting the destructive nature of long-term smoking on mental as well as physical health, the glowing hope is that many more lives in the future will be saved”.
The current Sheffield population, standing roughly at 575,000, means 1,713 a year on average die due to smoking in the city.