Arginine (Arg) has long been used to inhibit aggregation of proteins. Despite its frequent use in inhibition of aggregation, the exact mechanism of aggregation and the effect of Arg on the conformation and stability of proteins are still not well understood. In the present study, spectroscopic, calorimetric, and molecular dynamics methods have been used to understand the mechanism of inhibition of aggregation of alpha-lactalbumin (alpha-LA) by Arg along with its effect on stability of the protein. It is observed that although Arg inhibits aggregation of alpha-LA, it also decreases stability of the protein. The results suggest that strong favorable interactions between alpha-LA and guanidinium group of Arg decrease the stability of the protein. The results also suggest that the guanidinium group preferentially interacts with Gln, Asn and negatively charged residues through hydrogen bonding and electrostatic interactions. (C) 2014 Elsevier Ltd. All rights reserved.