A novel assay of gamma-globulin (gamma-IgG) with a sensitivity at the nanogram level is proposed based on the measurement of enhanced resonance light-scattering (RLS) signals resulting from the interaction of functionalized nano-HgS with gamma-globulin. At pH 5.03, the RLS signals of functionalized nano-HgS were greatly enhanced by gamma-globulin in the region of 200-700nm characterized by the peak around 362nm. Linear relationship can be established between the enhanced RLS intensity and gamma-globulin concentration in the range of 10-140ngml(-1). The limit of detection is 2.71ngml(-1). Based on this, a new direct quantitative determination method for gamma-globulin in blood serum samples without separation of human serum albumin (HSA) is established. The contents of gamma-IgG in blood serum samples were determined with recovery of 95.7-102.5% and R.S.D. of 1.6-2.4%. This method is proved to be very sensitive, rapid, simple and tolerance of most interfering substances.