Objective Using serum screening test and simulated gastrointestinal fluid digestion stability test to explore whether Oryza sativa recombinant human serum albumin (OsrHSA) has potential allergenicity. Methods In this study, 75 serum samples from patients with allergies to shrimp, wheat, house dust mites, eggs and milk, which containing specific IgE antibody concentrations greater than 3.5 kUA/L, as well as 4 healthy human serum samples were selected. Enzyme-linked immunosorbent assay was used to investigate whether OsrHSA could bind to allergen-specific IgE antibodies in the serum. The digestive stability test of the simulated gastrointestinal fluid of OsrHSA protein was carried out in accordance with the national food safety standard, detection of genetically modified organisms and derived products-simulated gastrointestinal fluid digestion stability test. Results Three sera allergic to milk had immunological cross-reactions with OsrHSA, indicating that the protein might have antigenic intersection with milk allergens. OsrHSA was completely digested within 15 s in the simulated gastric and intestinal fluid, indicating that the protein was easily digested. Conclusion OsrHSA has low potential allergenicity and people who are allergic to milk needs consideration.