Background: Clinical guidelines recommend RAS testing and BRAF testing in CRC and melanoma, respectively, to guide treatment (tx) decisions. However, there are limited data to support routine multi-gene profiling. This study evaluated the impact of multi-gene profiling on genomically-guided tx decisions in patients with CRC or melanoma. Methods: A retrospective cohort study using combined data from UUHC Electronic Warehouse, Huntsman Cancer Institute (HCI) tumor registry, ARUP laboratories, and Foundation Medicine. Included patients were treated at HCI for CRC or melanoma and had genomic profiling (2012-2016). The index date was date of first genomic profiling result and impact on practice was measured by rate of genomically-guided therapy use. Results: Among 127 genomically-profiled patients with CRC, 66 (52%) received therapy. Patients were predominantly male (64%), aged 57 years (median) at diagnosis, had advanced disease (52%), received three tx lines (mean) at baseline, and had three mutations (mean) detected. Actionable mutations, other than RAS,occurred in 43.9% of tested patients; and only 10.1% of these patients received genetically-guided tx. In the CRC cohort 55% are still receiving standard of care tx, and may benefit from testing results in the future. Among 186 genomically-profiled patients with melanoma, 123 (66.1%) received therapy. Patients were predominantly male (63%), aged 60 years (median) at diagnosis, diagnosed at earlier stages (68%), received two tx lines (mean) at baseline, and had two mutations (mean) detected. Actionable mutations, other than BRAF V600E/K, occurred in 14.6 % of tested patients; and only 5.6% of these patients received genetically-guided tx. In the Melanoma cohort 77% are still receiving standard tx. Actionable mutations and genomically guided tx decisions will be presented. Conclusions: Genomic profiling lead to modest increase in genetically-guided therapy. The incremental clinical and economic benefit of guideline-recommended testing needs further investigation by cancer type.