Data on more than 1,000 patients, released ahead of the world’s biggest cancer conference, showed a 14-month gulf in survival rates.
Doctors said location was probably a marker for a fundamentally different type of tumour.
And that separate treatments should be tailored for those on the left and right sides.
The study, to be presented at the American Society of Clinical Oncology’s annual conference, shows patients with advanced bowel cancer survived 33 months on chemotherapy if the tumour was on the left.
And just 14 months if it was on the right.
Dr Richard Goldberg, one of the researchers, from Ohio State University, told the BBC News website: “It was somewhat surprising the cancer on the right side had worse outcomes than on the left, regardless of what they were treated with.”
There was also a marked difference in how the tumours responded to different drugs.
The study showed Cetuximab was more helpful on the left-sided tumours, while Bevacizumab had an advantage on the right.
“There is potential for this to evolve into a practice-changing finding,” said Dr Goldberg.
Studies have already shown that bowel cancer is four distinct diseases - each of which has a separate prognosis.
Dr Alan Venook, from the University of California San Francisco, said: “I think we’ll be able to find [these]different versions distributed across the colon.
“We believe the side is really a surrogate marker for some biological explanation, and we’re hoping to tease that out over the next few months.”
One possible explanation for the difference between the left- and right- sided cancers goes back as far as the womb.
In the embryo stage of human development, the colon’s left side is built from the hind-gut and the right from the mid-gut.
So different parts of the colon have distinct origins, which could still be affecting the risk of cancer 60 years later, the researchers suggest.
Colorectal cancer causes nearly 700,000 deaths around the world each year.