Objective To explore the histological difference of spleen in BALB/c nude mouse with green fluorescent protein (GFP) at different ages, and compared with the histology of spleen in BALB/c nude mouse. Methods The spleens were gained, respectively, from 32 BALB/c nude mice with GFP and 32 BALB/c nude mice at assigned ages. The weight of spleen and spleen index were measured; the histology changes of the spleen were observed under light microscope. The sum of lymphocyte cells were counted and analyzed. Results The spleen index of 28 days BALB/c nude mouse with GFP are higher significantly than 14 days. Compared with 14 days BALB/c nude mouse with GFP, the sum of lymphocyte cells of 49 days, 70 days are reduced significantly. The sum of lymphocyte cells of 14 days, 28 days, 49 days, 70 days BALB/c nude mouse with GFP are higher significantly than 14 days, 28 days, 49 days, 70 days BALB/c nude mouse. Conclusion The GFP gene had some effect on the development and the immune function of the spleen in the BALB/c nude mouse with green fluorescent protein (GFP) at different ages.