Two of the main problems associated with matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) analysis of polymers are mass discrimination and poor reproducibility. This paper shows that the use of binary solvent systems is one of the causes of these problems. It was observed that the presence of a second solvent such as water in the PMMA solution could cause significant mass discrimination and varying polymer distributions, which can be varied by over 50% when PMMA 4K was used as the polymer sample. In general, a small amount of a second solvent tends to result in less severe mass discrimination but varying distributions, while large amounts of a second solvent are more likely to cause more systematic and severe mass discrimination. Except for a few cases, mass discrimination was observed to be against larger oligomers. Moreover, it was observed that this effect varies with the matrix, main solvent, and sample preparation used. The importance of this work is that it provides guidance for one to develop a better sample preparation protocol to minimize the mass discrimination and poor reproducibility problems. Several potential sources leading to water contamination were identified. Finally, a simple method to verify if amounts of a second solvent are sufficiently high to cause mass discrimination is also discussed.