Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with phenotypes including chronic bronchitis and emphysema. Hypoxia-inducible factor-1 alpha (HIF-1α) mediates cellular responses to hypoxia, while vascular endothelial growth factor (VEGF) promotes angiogenesis and erythropoietin (EPO) serves as a hypoxia-activated hematopoietic growth factor. Objectives: To determine the relationship among demographic characteristics, laboratory, and radiologic parameters, and HIF-1α, VEGF, EPO, LDH values of COPD phenotypes, and to reveal the relationship among the parameters. Methods: In this prospective study of 181 participants, clinical data, spirometry, and serum levels of HIF-1α, VEGF, and EPO were collected. ROC analysis determined optimal HIF-1α cutoffs for differentiating COPD from controls and for distinguishing COPD phenotypes. Correlations between HIF-1α and lung function parameters were assessed. Results: COPD patients exhibited significantly higher HIF-1α levels (954.25 ± 452.92 pg/mL) than controls (762.51 ± 393.99 pg/mL; p = 0.002). An optimal cutoff of 705.464 pg/mL yielded 66.67 % sensitivity and 62.79 % specificity for COPD diagnosis. For phenotype differentiation, a cutoff of 900 pg/mL distinguished emphysema from chronic bronchitis with 70 % sensitivity and 65 % specificity. HIF-1α showed a weak negative correlation with lung function (r = −0.17, p = 0.183) and did not vary significantly across GOLD stages (p = 0.462). A positive correlation with EPO levels was also noted. Conclusion: Elevated HIF-1α levels are associated with COPD and vary between its phenotypes, supporting its potential as a diagnostic biomarker. However, its limited correlation with disease severity suggests further research is needed.