Background: Colorectal cancer (CRC) is a heterogeneous disease with different molecular characteristics associated with many variables such as the sites from which the tumors originate or the presence or absence of chromosomal instability. Identification of such variables, particularly mutational hotspots, often carries a significant diagnostic and/or prognostic value that could ultimately affect the therapeutic outcome.Methods: High-throughput mutational analysis of 99 CRC formalin-fixed and paraffin-embedded (FFPE) cases was performed using the Cancer Hotspots Panel (CHP) v2 on the Ion Torrent (TM) platform. Correlation with survival and other Clinicopathological parameters was performed using Fisher's exact test and Kaplan-Meier curve analysis.Results: Targeted sequencing lead to the identification of frequent mutations in TP53 (65 %), APC (36 %), KRAS (35 %), PIK3CA (19 %), PTEN (13 %), EGFR (11 %), SMAD4 (11 %), and FBXW7 (7 %). Other genes harbored mutations at lower frequency. EGFR mutations were relatively frequent and significantly associated with young age of onset (p = 0.028). Additionally, EGFR or PIK3CA mutations were a marker for poor disease-specific survival in our cohort (p = 0.009 and p = 0.032, respectively). Interestingly, KRAS or PIK3CA mutations were significantly associated with poor disease-specific survival in cases with wild-type TP53 (p = 0.001 and p = 0.02, respectively).Conclusions: Frequent EGFR mutations in this cohort as well as the differential prognostic potential of KRAS and PIK3CA in the presence or absence of detectable TP53 mutations may serve as novel prognostic tools for CRC in patients from the Kingdom of Saudi Arabia. Such findings could help in the clinical decision-making regarding therapeutic intervention for individual patients and provide better diagnosis or prognosis in this locality.