People in any of the four treatment groups were more likely to die during their hospitalization than those not treated.
While the paper, published online in the Lancet medical journal, is not a trial created to assess the drug, it shows that the rush to use it around the world may be ill-advised. Significant numbers of doctors have been prescribing it without evidence.
The New York Times has reported there may be more to Trump's determined promotion of the drug as certain pharmaceutical companies will profit if it is accepted as a COVID-19 treatment.
The US Food and Drug Administration has said hydroxychloroquine should only be used for hospitalised Covid-19 patients or those in clinical trials.
Mr Trump said he was taking the drug despite public health officials warning that it could cause heart problems.
The results suggest these drugs are "not useful and may be harmful" in people hospitalized with COVID-19, professor Christian Funck-Brentano, of the Sorbonne University in Paris, wrote in a commentary published by the journal.
The study, the largest to-date looking at the efficacy of hydroxychloroquine and chloroquine, involved an examination of medical records for 96,000 people hospitalized between December 20 and April 14 at 67 facilities around the world for COVID-19 and treated with the antimalaria drugs.
The report further revealed that around 1 in 6 patients who were treated with hydroxychloroquine or chloroquine alone died in the hospital. Some of them are new antibody-based drugs that can neutralize the virus and provide short-lived immunity.
The statistics are not exactly comparable because, as this was not a trial, there were differences in the age, gender, general health and stage of illness of the patients.
Serious cardiac arrhythmias were also more common among patients receiving any of the four treatments.
The findings: Those given the drug alone had a 34% increased risk of dying and a 137% increased risk of heart arrhythmias.
Britain has ordered $42 million worth of hydroxychloroquine, despite numerous studies showing it is ineffective in treating Covid-19 and may even be more unsafe than doing nothing. A similar study is underway in the United Kingdom, to see if the medicine can protect medical personnel from infection. These risks remained significant even after the researchers controlled for factors such as smoking, underlying heart disease, diabetes, lung disease, or immune conditions.
"Furthermore, it is clear that high-profile endorsements of taking these drugs without clinical oversight are both misguided and irresponsible".
"Our data has very convincingly shown that across the world in a real-world population that this drug combination, whichever way you slice it or dice it, does not show any evidence of benefit, and in fact is immutably showing a signal of grave harm", said Dr. Mandeep Mehra, the study's lead author.