AbstractAmphoteric polyacrylamide (AmPAM) is a linear water-soluble polymer that has been applied in papermaking as an agent for flocculation, retention, filtration, and dry-strength improvement. However, AmPAM with different ranges of molecular weight (MW) have different properties in these processes. In this study, a series of AmPAMs were constructed with an anionic monomer, itaconic acid (IA), a cationic monomer, methacryloxyethyl-trimethyl ammonium chloride (DMC), and a main backbone of acrylamide (AM). Four factors influencing free radical polymerization, i.e., reaction temperature, pH, initiator load, and the concentration of monomers, were systematically investigated via an orthogonal test to determine their effects on the MW of AmPAM. Spectroscopy and isoelectric point assays were used to characterize the structure of the produced AmPAM, and the MW was assessed by calculating the viscosity. The reaction temperature had the greatest influence on the MW of AmPAM, followed by the solution pH and the initiator load. To determine the dry strength of papersheets containing AmPAM, the breaking length of handsheets was assessed after adding 0.5% AmPAM (based on fiber) with different MWs. The maximum value, 4.05 km, was 15.0% higher than the control and was obtained using AmPAM with a MW of 330 kDa.