Abstract Background The genetic locus 3p21.31 has been associated with severe coronavirus disease 2019 (COVID-19), but the underlying pathophysiological mechanism is unknown. Methods To identify intermediate traits associated with the 3p21.31 locus, we first performed a phenome-wide association study (PheWAS) with 923 phenotypes in 310 999 European individuals from the UK Biobank. For genes potentially regulated by the COVID-19 risk variant, we examined associations between their expression and the polygenic score (PGS) of 1263 complex traits in a meta-analysis of 31 684 blood samples. For the prioritized blood cell traits, we tested their associations with age and sex in the same UK Biobank sample. Results Our PheWAS highlighted multiple blood cell traits to be associated with the COVID-19 risk variant, including monocyte count and percentage (p = 1.07 × 10–8, 4.09 × 10–13), eosinophil count and percentage (p = 5.73 × 10–3, 2.20 × 10–3), and neutrophil percentage (p = 3.23 × 10–3). The PGS analysis revealed positive associations between the expression of candidate genes and genetically predicted counts of specific blood cells: CCR3 with eosinophil and basophil (p = 5.73 × 10–21, 5.08 × 10–19); CCR2 with monocytes (p = 2.40 × 10–10); and CCR1 with monocytes and neutrophil (p = 1.78 × 10–6, 7.17 × 10–5). Additionally, we found that almost all examined white blood cell traits are significantly different across age and sex groups. Conclusions Our findings suggest that altered blood cell traits, especially those of monocyte, eosinophil, and neutrophil, may represent the mechanistic links between the genetic locus 3p21.31 and severe COVID-19. They may also underlie the increased risk of severe COVID-19 in older adults and men.