Despite robust preclinical activity, CD47-targeting agents demonstrate limited single-agent efficacy in osteosarcomas. The purpose of our study was to investigate whether tumor size at baseline affects tumor-associated macrophage (TAM) response to CD47 mAb, as measured by ferumoxytol-MRI. Thirty female NOD SCID gamma mice and thirty BALB/c mice with small, medium-sized, and large 143B osteosarcoma xenografts or murine K7M2 tumors were treated with either CD47 mAb or PBS. All mice underwent MRI scans at baseline, one week after treatment, and after intravenous infusion of ferumoxytol nanoparticles. We measured tumor T2* relaxation times as a quantitative measure of nanoparticle retention in activated TAMs. Tumor ΔT2* was calculated as the difference between T2* post-treatment pre-contrast and T2* post-treatment post-contrast to quantify ferumoxytol enhancement. T2* and ΔT2* values were compared between treatment groups using regression models including treatment, tumor size, and their interaction. Histology served as a standard of reference. At baseline, tumors in CD47 mAb- and PBS-treated mice demonstrated no significant differences in T2* relaxation time, regardless of tumor size (all p > 0.05). After CD47 mAb therapy and ferumoxytol infusion, tumors treated with CD47 mAb demonstrated significantly shorter T2* relaxation times compared with PBS-treated tumors (all p < 0.001). The tumor ΔT2* enhancement was significantly higher in small tumors compared with large tumors (all p <  0.001), indicating higher nanoparticle accumulation in small tumors after CD47 blockade. Histopathology showed a significantly higher F4/80 ⁺ CD80 ⁺ TAM staining in CD47 mAb-treated small tumors compared with large tumors (all p  <  0.05). In conclusion, tumor size at baseline affects TAM response to CD47 mAb. Smaller osteosarcomas exhibit a more pronounced TAM response to CD47 mAb therapy compared with larger tumors.