Background We describe the association between high density lipoprotein cholesterol (HDL-C) concentration and computed tomography (CT)-measured fat depots. Methods We examined the cross-sectional associations between HDL-C concentration and intra-abdominal (IAF), abdominal subcutaneous (SCF), and thigh fat (TF) areas in 641 Japanese-American men and women. IAF, SCF, and TF were measured by CT at the level of the umbilicus and mid-thigh. The associations between fat area measurements and HDL-C were examined using multivariate linear regression analysis adjusting for age, sex, diabetes family history, homeostasis model assessment of insulin resistance (HOMA-IR), and body mass index (BMI). Non-linearity was assessed using fractional polynomials. Results Mean±standard deviation of HDL-C concentration and IAF in men and women were 1.30±0.34 mg/dL, 105±55.3 cm 2 , and 1.67±0.43 mg/dL, 74.4±46.6 cm 2 and differed significantly by gender for both comparisons ( P <0.001). In univariate analysis, HDL-C concentration was significantly associated with CT-measured fat depots. In multivariate analysis, IAF was significantly and non-linearly associated with HDL-C concentration adjusted for age, sex, BMI, HOMA-IR, SCF, and TF (IAF: β=−0.1012, P<0.001; IAF 2 : β=0.0008, P <0.001). SCF was also negatively and linearly associated with HDL-C (β=−0.4919, P =0.001). Conclusion HDL-C does not linearly decline with increasing IAF in Japanese-Americans. A more complex pattern better fits this association.