The article introduces PRSice, a new software tool for calculating, applying, evaluating, and plotting polygenic risk scores (PRS). PRSice is designed to automate and enhance the analysis of PRS, offering high-resolution options to identify the best-fit PRS at various P-value thresholds. The software can handle genotyped and imputed data, thin SNPs according to linkage disequilibrium, and incorporate ancestry-informative variables. It is written in R and integrated with PLINK-1.9 and bash scripts to minimize computational time. The authors demonstrate the use of PRSice through three studies: testing for shared genetic aetiology between schizophrenia and major depressive disorder (MDD), and investigating the genetic relationship between smoking status and MDD. They also perform a simulation study to estimate a significance threshold for high-resolution PRS studies. PRSice is freely available for download and can be used to expand the application of PRS in various genetic studies.The article introduces PRSice, a new software tool for calculating, applying, evaluating, and plotting polygenic risk scores (PRS). PRSice is designed to automate and enhance the analysis of PRS, offering high-resolution options to identify the best-fit PRS at various P-value thresholds. The software can handle genotyped and imputed data, thin SNPs according to linkage disequilibrium, and incorporate ancestry-informative variables. It is written in R and integrated with PLINK-1.9 and bash scripts to minimize computational time. The authors demonstrate the use of PRSice through three studies: testing for shared genetic aetiology between schizophrenia and major depressive disorder (MDD), and investigating the genetic relationship between smoking status and MDD. They also perform a simulation study to estimate a significance threshold for high-resolution PRS studies. PRSice is freely available for download and can be used to expand the application of PRS in various genetic studies.