<p>Full-dose systemic thrombolysis reduces haemodynamic decompensation in intermediate-high risk pulmonary embolism (PE) but increases bleeding risk, and its real-world safety profile in ICU settings remains incompletely characterised. We describe treatment selection patterns, safety outcomes, and resource utilisation associated with systemic alteplase versus unfractionated heparin (UFH) in ICU-managed intermediate-high risk PE. Prospective single-centre cohort; 80 adults with CTPA-confirmed intermediate-high risk PE (2020–2024), 40 per arm. Outcomes included mortality, bleeding, clinical deterioration, and ICU and hospital length of stay (LOS). Firth penalised logistic regression was used for binary outcomes with complete separation; negative binomial regression with covariate adjustment (age, APACHE II, Charlson Comorbidity Index, PESI class) for LOS. Clinicians preferentially selected alteplase for younger patients with greater PE-specific severity markers, and UFH for older, more comorbid patients with higher physiological derangement. Major bleeding was rare in both groups (UFH 2/40; alteplase 1/40; <i>P</i> = 0.781), with no intracranial or fatal events. Clinical deterioration occurred exclusively in the UFH group (17.5% vs 0%; <i>P</i> = 0.012), though most events represented rescue thrombolysis, structurally unobservable in the alteplase arm; no residual signal persisted after its exclusion (adjusted OR 0.77; <i>P</i> = 0.89). ICU LOS (rate ratio 0.70; <i>P</i> = 0.007) and hospital LOS (rate ratio 0.73; <i>P</i> = 0.019) were shorter with alteplase after covariate adjustment. In this prospective ICU cohort of carefully selected intermediate-high risk PE patients, systemic alteplase was associated with a favourable safety profile and shorter hospitalisation. These hypothesis-generating findings support prospective studies targeting ICU-managed intermediate-high risk PE.</p>