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Introduction: “Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. mean platelet volume, MPV) is high or low relative to its distribution. Methods: Offspring-parent (βOP) regression slopes were estimated by quantile regression, from which quantile-specific heritabilities (h2) were calculated (h2=2βOP/(1+rspouse)) for blood cell phenotypes in 3929 parent-offspring pairs from the Framingham Heart Study. Linear trends in βOP vs. percentiles of the phenotype distribution were tested using orthogonal polynomials. Results: Quantile-specific h2 (±SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted MPV distribution (Plinear=0.0001): 0.48±0.09 at the 10th, 0.53±0.04 at the 25th, 0.70±0.06 at the 50th, 0.74±0.06 at the 75th, and 0.90±0.12 at the 90th percentile. Quantile-specific h2 also increased with increasing percentiles of the offspring’s white blood cell (WBC), monocyte, and eosinophil distributions (Plinear=0.002, Plinear=0.01, and Plinear=0.0005, respectively). In contrast, heritibilities of red blood cell count (RBC), hematocrit (HCT), and hemoglobin (HGB) showed little evidence for quantile-dependence. Discussion/Conclusion" Quantile-dependent expressivity may explain several purported gene-environment interactions, including: 1) greater increases in WBC and PLT concentrations in subjects who are glutathione-S-transferase Mu1 (GSTM1) null homozygotes than GSTM1 sufficient when exposed to endotoxin; 2) significantly higher WBC count in AA homozygotes than carriers of the G-allele of the glutathione S-transferase P1 (GSTP1) rs1695 polymorphism at low but not high benzene exposure in shoe factory workers; 3) higher WBC counts in TT homozygotes than C-allele carriers of the interleukin-1β (IL1B) c.315C>T polymorphism after undergoing surgery for infective endocarditis but not before surgery.