Significant efforts have been made in recent years to identify more environmentally friendly and less dangerous alternatives N.,N.-Dimethylformamide (DMF) in solid phase peptide synthesis (SPPS). Several more environmentally friendly solvents were recommended as suitable candidates. However, it has proven difficult to find a clean solvent that fully matches the properties of DMF in SPPS. To this end, we have recently shown that green binary mixed solvents are viable alternatives to DMF, and have shown that the polarity and viscosity profile of a binary mixed solvent can be used to predict its usefulness in SPPS. In this report, we systematically examine how the composition of green binary solvent mixtures affects Fmoc removal, peptide coupling, and common side reactions in SPPS, and show that the purity profile in binary solvent mixtures is not adversely affected compared to DMF. In addition, we show that the only variation in the composition of the binary solvent mixture during synthesis is a new and simple tool for attenuating certain side reactions in SPPS, illustrated by the suppression of Arg-lactamization and aspartimide formation. When applied to the synthesis of the peptide therapeutic bivalirudin on a 7.5 mmol scale, we showed that the simple adjustment of the solvent ratio in a single synthesis step significantly suppressed a problematic side reaction of Arg-lactamization. These results underscore that green binary solvent mixtures can not only replace DMF in SPPS, but also offer novel solutions to mitigate common side reactions in SPPS.