Objectives: This study was designed to evaluate the effect of two different collagen cross linkers (GSE & SA) versus topical fluoride, and the effect of exposure time of these agents on management of root caries. Material and Method: 48 human premolar roots were used; the mesial or distal surface of each sample was ground flat to expose dentin surface, polished and then mounted on wax blocks. They were divided into 3 main groups (n=16); A1: received 6.5% GSE-treatment; A2: received 10% SA-treatment and A3: received topical 1.1%NaF gel. Each group was divided into 2 subgroups (n=8) according to treatment exposure time, where T1: was representing the short exposure time (10-min) and T2: was representing the long exposure time (30- min). Each group was pH-cycled for 3 constitutive days. Assessment was done using digital radiography (DR) and polarized light microscopy (PLM). Data was collected and statistically analyzed. Results: All agents used produced significant remineralization effect on the artificially demineralized root dentin following 30-min treatment, however the two collagen cross linkers produced significant mineralization effect after treatment for 10min. Conclusion: Using collagen cross linking agents could be of value