Abstract Objective VEXAS syndrome is a genetic disorder characterized by bone marrow failure and systemic inflammation, putting patients at risk for infections. This study comprehensively examines the prevalence of opportunistic infections in patients with VEXAS, evaluating their impact on clinical outcomes and potential preventive measures. Methods Patients with confirmed VEXAS were included. Survival analysis and logistic regression was used to identify associations between opportunistic infections and mortality. Infection rates (IR) for Pneumocystis jirovecii pneumonia (PJP) and alphaherpesviruses were calculated over a prospective 8-month observation period in relationship to prophylaxis. Results Out of 94 patients with VEXAS, 6% developed PJP, 15% had alphaherpesvirus reactivation, with varicella zoster virus (VZV) being the most common herpes virus, and 10% contracted a non-tuberculous mycobacteria (NTM) infection. Risk of death was significantly increased per month following a diagnosis of PJP (Hazard ratio (HR)=72.41, 95% CI 13.67-533.70) or NTM (HR=29.09, 95% CI 9.51-88.79). Increased odds for death were also observed in patients with a history of HSV reactivation (Odds ratio (OR) =12.10, 95% CI 1.29-114.80) but not in patients with VZV (OR= 0.89, 95% CI 0.30-2.59). Prophylaxis for PJP (IR 0.001 vs 0 per person day, p<0.01) and VZV (IR 0.006 vs 0 per person day, p=0.04) markedly decreased infection rates with a number needed to treat of 4 and 7, respectively. Conclusion Opportunistic infections are common in patients with VEXAS. Patients who develop PJP, HSV, or NTM are at increased risk for death. Prophylaxis against PJP and VZV is highly effective.