Our Lab established next-generation sequencing (NGS) in 2017 to detect molecular alterations in solid tumors for diagnosis and to identify therapeutic targets. Our Lab is referral for various regional Hospitals with a high heterogeneity of pre-analytical conditions. The most frequent cancer types requiring NGS-based testing in our Lab are non-small cell lung cancer and colon cancer. From early 2020 to late 2021, the diagnostic flow was based on Ion GeneStudio S5 System and Oncomine Dx Target Test Assay, with about 1800 patients analyzed. Two lab technicians and one molecular biologist were full-day dedicated to the analysis. The plan was designed to complete the whole analytical process in one week, from handling of tumor samples to sequencing, with and overall turn-around-time of 7 working days. This workflow was certified by EMQN-GENQA and QUIP programs. Since November 2021, the workflow is based on Ion Torrent Genexus platform and Oncomine Precision Assay GX. Training for lab technicians and for bioinformatics analysis was fast and no specific critical items were identified. Since then, >250 patients have been analyzed, with no changes in the personnel employed. The time for the whole analytical process decreased from 4 to 3 working days, due to the completely automatic library preparation, and the overall turn-around-time is 5 working days. The shortening of the time allocated for the procedure allowed a better management of human resources. Moreover, it is now possible to plan two runs of sequencing within the same week, which is an emerging need to guarantee the weekly plan of the workflow despite the increasing number of cases to be analyzed. The rate of failure due to insufficient material or inadequate quality of nucleic acids is comparable between the two platforms and assays. As to concern bioinformatics, the Oncomine Precision Assay GX allows a higher level of information in terms of types of analysis (CNV) and quality of detection of gene fusions.