The objective of this study was to validate the genetic selection for resistance to streptococcosis under experimental challenge conditions in a commercial population of Nile tilapia . Further, effects of using two different routes of infection of Streptococcus agalactiae; intraperitoneal injection (IP) and cohabitation with the shedder fish (cohab), on the genomic parameters, prediction accuracy and response to selection are compared . The comparison was made between two different lines of fish; one selected for S. agalactiae resistance for one generation and randomly mated for two generations (to mimic the multiplication activities occurring in distribution channels and hatcheries); and the other unselected . 1,500 fish, each from these two lines, were used for the experimental challenge test . Survival analysis using Kaplan-Meier estimators and Hazard's ratio was used to quantify differences in mortality between the two lines . Further genomic analysis was performed with 2,684 fish and 35,745 SNPs using both univariate and bivariate GBLUP models . Genetic selection for resistance to S. agalactiae led to the significant (p <.001) reduction in the risk of death by 65% in the selected line, compared to the unselected line . Similarly, the risk of death via cohabitation route of infection significantly (p <.01) decreased by 80%, compared to IP . The genetic correlation between these two routes of infection was ~0.9 . Genetic selection changed the impact of the routes of infection, with the change in the distribution of estimated breeding values and the gain of 3.04 ± 1.25 days as selection response (p <.05).