BACKGROUND: Considerable progress of ultrasound simulation on blood has enhanced the characterizing of red blood cell (RBC) aggregation. OBJECTIVE: A novel simulation method aims at modeling the blood with different RBC aggregations and concentrations is proposed. METHODS: The modeling process is as follows: (i) A three-dimensional scatterer model is first built by a mapping with a Hilbert space-filling curve from the one-dimensional scatterer distribution. (ii) To illustrate the relationship between the model parameters and the RBC aggregation level, a variety of blood samples are prepared and scanned to acquire their radiofrequency signals in-vitro. (iii) The model parameters are determined by matching the Nakagami-distribution characteristics of envelope signals simulated from the model with those measured from the blood samples. RESULTS: Nakagami metrics m estimated from 15 kinds of blood samples (hematocrits of 20%, 40%, 60% and plasma concentrations of 15%, 30%, 45%, 60%, 75%) are compared with metrics estimated by their corresponding models (each with different eligible parameters). Results show that for the three hematocrit levels, the mean and standard deviation of the root-mean-squared deviations of m are 0.27 ± 0.0026, 0.16 ± 0.0021, 0.12 ± 0.0018 respectively. CONCLUSION: The proposed simulation model provides a viable data source to evaluate the performance of the ultrasound-based methods for quantifying RBC aggregation.