Quantifying trace microRNAs (miRNAs) is extremely important in a number of biomedical applications but remains a great challenge. Here we present an enzyme-free amplification strategy called plasmon-enhanced hybridization chain reaction (PE-HCR) for quantifying trace miRNAs with an outstanding linear range from 1 fM to 1 pM (r(2) = 0.991), along with a detection limit of 0.043 fM (1300 molecules in 50 μL of sample). The merits of the PE-HCR assay, including high sensitivity and specificity, quantitative detection, no enzyme involvement, low false positives, and easy-to-operate procedures, have been demonstrated for high-confidence quantification of the contents of miRNAs in even single cancer cells. The PE-HCR assay may open up new avenues for highly sensitive quantification of biomarkers and thus should hold great potentials in clinical diagnosis and prognosis.