Researchers writing in the Journal of the National Cancer Institute studied 100,000 people and found the benefits of daily aspirin were 'considerably lower' than detected in previous research.
Although the overall benefit still outweighs the risks, 'important questions remain about the size of this potential benefit' said the team from the American Cancer Society in Atlanta.
A previous pooled analysis of RCTs found taking daily aspirin for five years or more could slash a person's risk of dying from cancer by 37%.
In this latest study, researchers compared observed cases of cancer among those who took aspirin and those who did not.
They found the risk of dying from cancer was only 16% lower among those who took aspirin, regardless of how long they took it for. This was mainly due to fewer cases of gastrointestinal cancers.
Eric Jacobs PhD and colleagues said: 'Our results are consistent with an association between recent daily aspirin use and modestly lower cancer mortality.'
They admitted that the study, which was observational rather than an RCT, may have underestimated or overestimated reductions in cancer deaths.
But researchers concluded: 'Even a relatively modest benefit with respect to overall cancer mortality could still meaningfully influence the balances of risk and benefits of prophylactic aspirin use.'
In an editorial, Dr John Baron of the University of North Carolina said the findings strengthened the idea that aspirin lowers risk of cancer deaths.
But he warned: 'As for any preventative intervention, the benefits must be balanced against the risks, particularly when the benefits are delayed whereas the risks are not.'