Objective: Animal studies suggest that HDL (high-density lipoprotein) regulates proliferation and differentiation of hematopoietic stem cells. Using a Mendelian randomization approach, we tested the hypothesis that low HDL cholesterol is associated with high white blood cell counts. Approach and Results: We included 107 952 individuals aged 20 to 100 years from the Copenhagen General Population Study with information on HDL cholesterol, white blood cell counts, and 9 genetic variants associated with HDL cholesterol. In multivariable-adjusted observational analyses, HDL cholesterol was inversely associated with white blood cell counts. On a continuous scale, a 1-mmol/L (39 mg/dL) lower HDL cholesterol was associated with 5.1% (95% CI, 4.7%-5.4%) higher leukocytes, 4.5% (95% CI, 4.0%-4.9%) higher neutrophils, 5.7% (95% CI, 5.3%-6.1%) higher lymphocytes, 5.7% (95% CI, 5.3%-6.2%) higher monocytes, 14.8% (95% CI, 13.9%-15.8%) higher eosinophils, and 3.9% (95% CI, 3.1%-4.7%) higher basophils. In age- and sex-adjusted genetic analyses using the inverse-variance weighted analysis, a 1-mmol/L (39 mg/dL) genetically determined lower HDL cholesterol was associated with 2.2% (95% CI, 0.3%-4.1%) higher leukocytes, 4.3% (95% CI, 1.6%-7.1%) higher lymphocytes, 4.3% (95% CI, 2.6%-6.1%) higher monocytes, and 4.8% (95% CI, 1.2%-8.5%) higher eosinophils. Overall, the genetic associations were robust across sensitivity analyses and replicated using summary statistics from the UK Biobank with up to 350 470 individuals. Conclusions: Genetic and hence lifelong low HDL cholesterol was associated with high peripheral blood leukocytes, including high lymphocytes, monocytes, and eosinophils. The concordance between observational and genetic estimates and independent replication suggest a potential causal relationship.