Background: Social media has become a vital tool for health care providers to quickly share information. However, its lack of content curation and expertise poses risks of misinformation and premature dissemination of unvalidated data, potentially leading to widespread harmful effects due to the rapid and large-scale spread of incorrect information., Objective: We aim to determine whether social media had an undue association with the prescribing behavior of hydroxychloroquine, using the COVID-19 pandemic as the setting., Methods: In this retrospective study, we gathered the use of hydroxychloroquine in 48 hospitals in the United States between January and December 2020. Social media data from X/Twitter was collected using Brandwatch, a commercial aggregator with access to X/Twitter's data, and focused on mentions of "hydroxychloroquine" and "Plaquenil." Tweets were categorized by sentiment (positive, negative, or neutral) using Brandwatch's sentiment analysis tool, with results classified by date. Hydroxychloroquine prescription data from the National COVID Cohort Collaborative for 2020 was used. Granger causality and linear regression models were used to examine relationships between X/Twitter mentions and prescription trends, using optimum time lags determined via vector auto-regression., Results: A total of 581,748 patients with confirmed COVID-19 were identified. The median daily number of positive COVID-19 cases was 1318.5 (IQR 1005.75-1940.3). Before the first confirmed COVID-19 case, hydroxychloroquine was prescribed at a median rate of 559 (IQR 339.25-728.25) new prescriptions per day. A day-of-the-week effect was noted in both prescriptions and case counts. During the pandemic in 2020, hydroxychloroquine prescriptions increased significantly, with a median of 685.5 (IQR 459.75-897.25) per day, representing a 22.6% rise from baseline. The peak occurred on April 2, 2020, with 3411 prescriptions, a 397.6% increase. Hydroxychloroquine mentions on X/Twitter peaked at 254,770 per day on April 5, 2020, compared to a baseline of 9124 mentions per day before January 21, 2020. During this study's period, 3,823,595 total tweets were recorded, with 10.09% (n=386,115) positive, 37.87% (n=1,448,030) negative, and 52.03% (n=1,989,450) neutral sentiments. A 1-day lag was identified as the optimal time for causal association between tweets and hydroxychloroquine prescriptions. Univariate analysis showed significant associations across all sentiment types, with the largest impact from positive tweets. Multivariate analysis revealed only neutral and negative tweets significantly affected next-day prescription rates., Conclusions: During the first year of the COVID-19 pandemic, there was a significant association between X/Twitter mentions and the number of prescriptions of hydroxychloroquine. This study showed that X/Twitter has an association with the prescribing behavior of hydroxychloroquine. Clinicians need to be vigilant about their potential unconscious exposure to social media as a source of medical knowledge, and health systems and organizations need to be more diligent in identifying expertise, source, and quality of evidence when shared on social media platforms., (©Scott A Helgeson, Rohan M Mudgalkar, Keith A Jacobs, Augustine S Lee, Devang Sanghavi, Pablo Moreno Franco, Ian S Brooks, National COVID Cohort Collaborative (N3C). Originally published in JMIR Infodemiology (https://infodemiology.jmir.org), 18.11.2024.)