A recognized paradigm for the therapeutic action of intravenous immunoglobulin (IVIG) in immune thrombocytopenia (ITP) involves up-regulation of the inhibitory Fcγ receptor (FcγRIIB) in splenic macrophages. However, published data have indicated that opposing results are obtained when using FcγRIIB-deficient mice on different strain backgrounds. Herein we show BALB/c FcγRIIB(-/-) and wild-type, with or without spleens, all recover ITP with similar dynamics after IVIG (1 g/kg) treatment; however, this was not the case for C57BL/6 (B6) FcγRIIB(-/-). In investigating this conundrum, we found that wild-type B6 mice are much less sensitive than BALB/c to IVIG-mediated amelioration of ITP, requiring approximately 2- to 2.5-fold more IVIG than BALB/c. When using 2.5 g/kg IVIG in FcγRIIB(-/-) B6 mice, amelioration of ITP was as in wild-type in all animals. Our findings led us to the conclusion that different strains of mice respond differently to IVIG and that FcγRIIB plays no role in the mechanism of effect of IVIG in experimental ITP.