Background <p>The role of thrombolysis in out-of-hospital cardiac arrest (OHCA) remains uncertain, with limited evidence of benefit. This study evaluated whether prehospital administration of Tenecteplase improves outcomes in patients with presumed thromboembolic OHCA.</p> Methods <p>A retrospective cohort study was conducted using a regional cardiac arrest registry comprising 2,829 adult OHCA cases. Of these, 171 patients received Tenecteplase in the prehospital setting. Logistic regression was used to assess the association between thrombolysis and two outcomes: 30-day survival (primary) and return of spontaneous circulation (ROSC) at hospital arrival (secondary), adjusting for relevant confounders.</p> Results <p>Thirty-day survival was 4% in the thrombolysis group versus 10% in controls. Adjusted odds of survival were significantly lower with thrombolysis (OR 0.08, 95% CI 0.04–0.19), as were odds of achieving ROSC (OR 0.21, 95% CI 0.14–0.33). Shockable rhythm (OR 15.89) and witnessed arrest (OR 1.99) were strong independent predictors of survival. Model fit was moderate (McFadden’s R² = 0.27).</p> Conclusion <p>Prehospital thrombolysis with Tenecteplase was not associated with improved survival or ROSC in OHCA and may be linked to worse outcomes. These findings highlight a lack of sustained benefit associated with empiric thrombolysis based on suspected thromboembolic cause in OHCA, and raise questions about its routine prehospital use without definitive diagnosis.</p>