Background: ERBB2 amplification (HER2amp) is evolving as a distinct subset of mCRC with therapeutic implications. Although seen in 3-4% of mCRC in tumor tissue, little is known about occurrence of HER2amp in ctDNA. The purpose of this study was to assess the value of ctDNA in detection of HER2amp in blood and to delineate its landscape in mCRC. Methods: We performed a retrospective analysis of mCRC patients (pts) who underwent plasma-derived NGS of ctDNA in a CLIA-certified lab (Guardant Health, Inc.) using a high sensitivity assay that reports copy-number variations using pre-specified algorithms. Pts with no detectable alterations were excluded. The cohort was divided into 2 groups: HER2amp and ERBB2 non-amplified (HER2NA). Descriptive statistics and Fisher’s exact test were used. Results: Between 5/2014 and 5/2016, 1625 mCRC pts had a ctDNA NGS assay and of these 1387 met our inclusion criteria. Among these, HER2amp was seen in 69 pts (4.9%, 95%CI: 3.9 – 6.3). HER2amp were found to be enriched in RAS wild-type (WT) (6.4% v 2.9%, OR 2.3, P = 0.002) and RAS/BRAFV600E WT (6.9% v 2.7%; OR 2.7, P < 0.001). When co-existing with RAS mutations, HER2amps were seen more with sub-clonal ( < 50% relative mutation allele frequency) RAS mutations than clonal RAS mutations (6.6% v 2.1%, OR 3.1, P = 0.03). The most common co-occurring mutations were TP53 (77%), APC (59%), EGFR (25%), PIK3CA (25%) and KRAS (23%). HER2 (13% v 5%, OR 2.6, P = 0.017) and TP53 (77% v 62%, OR 2.1, P = 0.011) mutations co-occurred more frequently with HER2amp than with HER2NA cases. No significant association was seen with PIK3CA, EGFR and APC mutation status. Conclusions: In one of the largest series of CRC pts with ctDNA NGS, ERBB2 amplification were confirmed to be enriched in RAS/BRAF WT mCRC. In these pts, co-existing clonal RAS mutations are uncommon, but concurrent PIK3CA and ERBB2 mutations are present in a sizable minority of cases. These findings may have implications for anticipated innate/acquired resistance mechanisms to HER2-targeting therapies under evaluation for CRC.