ABSTRACT Background and objective:  The role of β2‐adrenergic receptor (ADRB2) in pulmonary oxygenation has been ascertained during altitude acclimatization, physical performance and lung fluid clearance, but little is known about its association with high‐altitude pulmonary oedema (HAPE), a non‐cardiogenic pulmonary oedema. Methods:  In a case–control study, 110 unrelated HAPE patients (HAPE‐p) and 143 unrelated HAPE‐resistant (HAPE‐r) controls matched on age and ethnicity were used to examine the association between eight single nucleotide polymorphisms (SNP) and disease. The eight SNP including three tag‐SNP were genotyped from promoter and exonic regions of ADRB2. Robust methods for predicting geneotype–phenotype interactions, for example, multidimensional reduction (MDR) and moving‐window haplotype analysis were applied. Results:  The haplotypes from 46A/G and 79C/G SNP of ADRB2 were associated with HAPE. The MDR model depicting disease association through genotype–genotype and genotype–phenotype interaction included SNP 46A/G, 79C/G and 523C/A. Its haplotype 46G_79C_523C was significantly overrepresented in HAPE‐r (P = 0.0001; χ2 = 14.95; OR = 4.52; 95% CI: 1.98–10.3). The global haplotype test showed significant association with HAPE (LRχ2 = 86.69, P < 0.0001). A moving‐window analysis revealed that haplotype –367C/T_46A/G_79C/G differed significantly between HAPE‐p and HAPE‐r (LRχ2 = 22.5, P = 0.002). The MDR model depicted SNP 46A/G, 79C/G and 523C/A as the best combination predicting disease. Conclusions:  The haplotypes of ADRB2 consisting of the SNP, 46A/G and 79C/G, have a greater power for predicting HAPE. This case–control study examined the association between eight important single nucleotide polymorphisms (SNP) of ADRB2 and high‐altitude pulmonary oedema (HAPE). Methods for predicting geneotype–phenotype interactions such as multidimensional reduction and moving‐window haplotype analysis were applied. The haplotypes consisting of common SNP, 46A/G and 79C/G were associated with HAPE.