BackgroundThe risk factors for mortality might differ between patients with acute exacerbation of chronic pulmonary heart disease in plains and plateaus, while there is a lack of evidence.MethodPatients diagnosed with cor pulmonale at Qinghai Provincial People’s Hospital were retrospectively included between January 2012 and December 2021. The symptoms, physical and laboratory examination findings, and treatments were collected. Based on the survival within 50 days, we divided the patients into survival and death groups.ResultsAfter 1:10 matching according to gender, age, and altitude, 673 patients were included in the study, 69 of whom died. The multivariable Cox proportional hazards analysis showed that NYHA class IV (HR = 2.03, 95%CI: 1.21–3.40, P = 0.007), type II respiratory failure (HR = 3.57, 95%CI: 1.60–7.99, P = 0.002), acid-base imbalance (HR = 1.82, 95%CI: 1.06–3.14, P = 0.031), C-reactive protein (HR = 1.04, 95%CI: 1.01–1.08, P = 0.026), and D-dimer (HR = 1.07, 95%CI: 1.01–1.13, P = 0.014) were risk factors for death in patients with cor pulmonale at high altitude. Among patients living below 2500 m, cardiac injury was a risk factor for death (HR = 2.47, 95%CI: 1.28–4.77,P= 0.007), while no significant association was observed at ≥ 2500 m (P= 0.057). On the contrary, the increase of D-dimer was only a risk factor for the death of patients living 2500 m and above (HR = 1.23, 95% CI: 1.07–1.40,P= 0.003).ConclusionNYHA class IV, type II respiratory failure, acid-base imbalance, and C- reactive protein may increase the risk of death in patients with cor pulmonale. Altitude modified the association between cardiac injury, D-dimer, and death in patients with cor pulmonale.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12890-023-02509-1.