The pain felt during injection, typically delivered via a hypodermic needle as a single bolus, is associated with the pressure build-up around the site of injection. It is hypothesized that this counterpressure is a function of the target tissue as well as fluid properties. Given that novel vaccines target different tissues (muscle, adipose, and skin) and can exhibit a wide range of fluid properties, we conducted a study of the effect of volumetric flow rate, needle size, viscosity and rheology of fluid, and hyaluronidase as an adjuvant on counterpressure build-up in porcine skin and muscle tissues. In particular, we found a significant increase in counterpressure for intradermal (ID) injections compared to intramuscular (IM) injections, by an order of magnitude in some cases. We also showed that the addition of adjuvant affected the tissue back pressure only in case of subcutaneous (SC) injections. We observed that the volumetric flow rate plays an important role along with the needle size. This study aims to improve the current understanding and limitations of liquid injectability via hypodermic needles, however, the results also have implications for other technologies, such as intradermal jet injection where a liquid bleb is formed under the skin.