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Highly sensitive multiplex biomarker detection is critical for the early diagnosis of liver cancer. Here a surface-enhanced Raman scattering (SERS) frequency-shift immunoassay is developed for detection of liver cancer biomarkers α-fetoprotein and Glypican-3 down to sub-picomolar concentrations in saline solution. A high temperature modification of the Tollen's method affords silver nanoparticle films with excellent SERS response upon which ordered domains of Raman reporters are chemisorbed by micro-contact printing. Shifts in the reporters SERS spectrum in response to a bound antibody's biomarker recognition constitutes the frequency shift assay, exhibiting here exceptional sensitivity and specificity and shown to function in fetal calf serum and in the serum of a patient with hepatocellular carcinoma.