Relationships between quantitative ultrasound (QUS), density (bone volume density [BV/TV]), and trabecular architecture were investigated in 69 calcaneal cancellous bone cubes. Ultrasound signal velocity, phase velocity, attenuation, and broadband ultrasonic attenuation (BUA) measurements were made along the mediolateral axis. Density and architectural parameters were measured using microcomputed tomography (μCT). Density yielded the best correlations with QUS (r2 = 73–77%). Of the individual architectural parameters, correlations with QUS were highest for the Structure Model Index (SMI), a parameter quantifying the relative proportion of rods and plates (r2 = 57–63%). After adjustment for density, significant associations with QUS remained for SMI, trabecular spacing (Tb.Sp), and trabecular number (Tb.N), although the variance in QUS attributable uniquely to individual architectural parameters was at best 4%. In multivariate regression models, combinations of density and architectural parameters explained 76–82% of the variance in QUS, representing an r2 increase of, at most, 8% compared with using density alone. However, multivariate models using combinations of architectural parameters alone (i.e., density excluded) also had a good predictive ability for QUS (r2 = 73–81%). Thus, although these data show modest but significant density-independent relationships between QUS and trabecular architecture in the human calcaneus for the first time, the causal relationships behind the variation in acoustic properties remain obscure. Given the relative weakness and complexity of the emerging associations between QUS and architecture, it is prudent to regard QUS measurements in calcaneal bone primarily as an indicator of bone density.