Antibody-based immunoassays remain the most popular methods for detecting and identifying the location of proteins and other biomolecules in biological samples. A major limitation in the use of immunoassays is that the low abundance of a given target molecule in a sample often necessitates signal amplification before detection is possible. Amplification can be achieved using conjugated enzymes. Current amplification methods have several drawbacks: 1) high background, 2) reduced spatial resolution, 3) lack of multiplexity, and 4) unsuitable for use with large-volume samples in new tissue expansion and clearing techniques. To overcome many of these limitations, we adapt hybridization chain reaction (HCR) technology to amplify immunosignals. We here describe immunosignal HCR (‘isHCR’) and demonstrate the use of HCR in a variety of immunoassays. The streptavidin-biotin interaction can be utilized for the typical isHCR application. isHCR uses label-free streptavidin, which allows the attachment of synthesized 5’- biotinylated DNA HCR initiators to the biotinylated antibodies. These initiators can then be elaborated with fluorescent DNA HCR amplifiers for signal detection. Alternatively, the DNA HCR initiators can be conjugated directly onto antibodies, therefore omitting the streptavidin-biotin interaction.