Direct determination of ng g(-1) level of selenium by ICP-MS is complicated because of the presence of serious spectral interferences, and the high first ionization energy of Se (9.75 eV) also results in low analytical sensitivity. In this study, a reliable method for accurate determination of Se in biological samples using CH4-Ar mixed plasma-DRC-MS was evaluated. The predominant interfering Ar-40(2)+ (from ion source) on the most abundant Se-80 isotope was successfully eliminated by the charge transfer reaction using methane as DRC gas. The minor interferences of oxide or hydroxides ions (Zn-64 O-16(+), (NiO+)-Ni-64-O-16 and (CuOH+)-Cu-63-O-16) and double charged ions (Tb-159(2+), Dy-160,161(2+) and Gd-160(2+)) originating from sample matrix were decreased down to 50% using CH4-Ar mixed gas plasma instead of the conversional pure Ar-ICP. Meanwhile, the poor sensitivity of Se+ was improved by a factor of 3 due to the carbon-enhancement effect in CH4-Ar mixed gas plasma. In addition, to avoid the interference (BrH+)-Br-79 on Se-80(+), an elaborate evaporation procedure was used to remove the Br from the digestion solution. The proposed method was applied to direct determination of Se in fifty biologically related SRMs. Our results showed that the values of most SRMs were found to agree well with the certified or recommended values. This method has great potential for the determination of trace or trace level of Se in various biological samples.