<p>Upadacitinib, a selective Janus kinase (JAK) inhibitor, has become an effective therapeutic option for rheumatoid arthritis (RA). However, venous thromboembolism (VTE) represents a potentially life-threatening complication associated with JAK inhibition, and uncertainties remain regarding the risk of specific VTE subtypes with upadacitinib, including non-fatal pulmonary embolism (nPE), non-fatal deep vein thrombosis (nDVT), and concurrent pulmonary embolism and deep vein thrombosis (cPE-DVT). This meta-analysis was performed to systematically assess the risks of these individual VTE subtypes in patients with RA receiving upadacitinib relative to comparator treatments. We systematically searched databases, including PubMed, Embase, and the Cochrane Library, for relevant randomized controlled trials (RCTs) in RA patients that reported VTE and its subtypes. Meta-analysis was conducted using the Mantel-Haenszel (M-H) fixed-effects model to calculate risk ratios (RR) with 95% confidence intervals (CI) due to low heterogeneity. A total of 4 RCTs involving 4201 patients were included in this meta-analysis. The results showed that no significant differences were observed between the upadacitinib and control groups in the risk of total VTE (0.79% vs. 0.78%; RR=0.93, 95%CI: 0.47–1.83, P=0.82), nPE (0.32% vs. 0.42%; RR=0.72, 95%CI: 0.28–1.83, P=0.49), nDVT (0.34% vs. 0.33%; RR=0.97, 95%CI: 0.32–2.96, P=0.96), or cPE-DVT (0.20% vs. 0.11%; RR=1.32, 95%CI: 0.20–8.62, P=0.77). Heterogeneity was absent across all analyses (I² = 0% for all outcomes). In this meta-analysis of RCTs, upadacitinib did not demonstrate a significantly increased risk of VTE or its subtypes compared to controls in the studied RA population. Despite the low overall incidence and lack of signal in this cohort, the potential VTE risk highlighted by the FDA boxed warning necessitates careful patient selection based on comorbidities and dosage.</p> Graphical abstract <p></p> <p>This meta-analysis of four randomized controlled trials (4,201 patients) evaluated the risk of venous thromboembolism (VTE) and its subtypes (non-fatal pulmonary embolism [nPE], non-fatal deep vein thrombosis [nDVT], concurrent PE-DVT [cPE-DVT]) in rheumatoid arthritis (RA) patients treated with upadacitinib versus active comparators. No significant differences were observed for total VTE or any VTE subtype. Despite the low incidence in selected trial cohorts, these findings require caution alongside the FDA class-wide boxed warning for JAK inhibitors.</p>