The biocompatibility of NPs to blood cells is a key issue when these NPs are planned for intravenous application because of potential contact with blood cells and proteins. In this work, γ-Fe2O3 NPs (~ 9 nm) and their poly(N,N-dimethylacrylamide) (PDMA) and SiO2-coated derivatives (γ-Fe2O3@PDMA and γ-Fe2O3@SiO2, respectively) were investigated. It was detected that both PDMA and SiO 2 coatings decreased NPs’ aggregation in the buffer solutions, as well as in cell culture medium. Neither neat γ-Fe2O3 NPs nor their coated derivatives possessed hemolytic activity toward red blood cells. There was no significant loss of body weight observed after the intravenous injection to laboratory mice. The immune response to the injected NPs was assessed by the ELISA measuring. No antibodies of the IgM class were detected, which suggests lack of acute inflammation. On the 35th day of the experiment, there was a rise in the content of the anti-OVA IgG noticed in all three types of the NPs; however, this rise was lower compared to that induced by the positive control. The injected NPs were found to be spread and settled in the pouch cavity, and none of the tested NPs caused vascular damage or distinct signs of inflammation. Summarizing, γ-Fe2O3 NPs coated with the PDMA or SiO2 manifested good compatibility with blood cells in in vitro and in vivo investigations.