On September 9, 2021, the US Food and Drug Administration (FDA) issued a drug safety communication and required revisions to the Boxed Warning for Xeljanz/Xeljanz XR (tofacitinib), Olumiant (baricitinib), and Rinvoq (upadacitinib) to include information about the risk of serious heart-related events, cancer, blood clots, and death. The Boxed Warning was based on a large safety randomized clinical trial of tofacitinib, but neither baricitinib nor upadacitinib has been studied in similar large safety clinical trials. To evaluate characteristics of adverse event (AE) reporting of tofacitinib/XR, baricitinib, and upadacitinib to the FDA. We analyzed the public FDA's Adverse Event Reporting System data to examine reported AEs that were related to any of the 3 drugs between January 1, 2019, and September 30, 2021. Both brand and generic names of these drugs were used to identify these AEs. Frequencies of AE reports were evaluated by patient demographics (age and sex), type of reporter, reporter region, seriousness, and reactions related to death, cardiovascular, cancer, and blood clots. Chi-square tests were used to compare the proportion of characteristics of AEs between these drugs at < 0.05. We identified 56,833 AE reports of tofacitinib/XR, 2,318 reports of baricitinib, and 5,359 reports of upadacitinib. Higher proportions of patients reporting AEs for tofacitinib/XR were older and female than for baricitinib and upadacitinib. Higher proportions of tofacitinib/XR and baricitinib AEs were reported by health professionals than for upadacitinib. Higher proportions of upadacitinib AEs were in the United States and more serious than those of tofacitinib/XR and baricitinib AEs (all group and paired comparisons at < 0.05). Regarding reactions, baricitinib AEs had highest proportions of death (7.2%) and cancer-related (4.1%) events, whereas tofacitinib/XR AEs had the highest proportions of cardiovascular-related (14.1%) and blood clot-related (14.8%) events. Although baricitinib and upadacitinib are in the same drug class as tofacitinib/XR, their risk of serious cardiovascular events, cancer, blood clots, and death might not be similar. Findings from this hypothesis-generating study suggest that there may be differential AEs between Janus kinase inhibitors, and therefore, future research for robust comparative safety is warranted.