Background: NRG1 rearrangements are oncogenic drivers across several tumor types. Chimeric proteins encoded by NRG1 fusions activate HER3, resulting in heterodimerization with HER2 and activation of downstream signaling. Preclinical and preliminary clinical data suggest that targeting HER3 may be an effective treatment strategy for patients with NRG1 fusion-positive tumors. We aimed to describe the clinical and genomic characteristics of patients identified at our institution with NRG1 fusions. Methods: We analyzed results from prospective targeted exome and/or RNA sequencing performed at Memorial Sloan Kettering between 2014-2018 involving > 30,000 samples. NRG1 fusion-positive tumors were identified and these cases were manually reviewed. Results:NRG1 fusions were detected in 24 patients. Cancer types included lung (N = 9), pancreas (N = 7), breast (N = 5), prostate (N = 1), gallbladder (N = 1), diffuse large B-cell lymphoma (N = 1), and cancer of unknown primary (N = 1). 6/9 lung cancers had mucinous differentiation. The majority of patients were Caucasian (N = 17), half were female (N = 12) and ages ranged from 24-82 years-old. Targeted exome sequencing identified the fusion in 10/23 cases tested, including 2 not confirmed by RNA. The remaining 14 were detected using RNA. Fusion partners included CD74 (N = 6), SLC3A2 (N = 2), SDC4 (N = 2), ATP1B1 (N = 2), FOXA1 (N = 1), SLCA4 (N = 1), ROCK1 (N = 1), TNKS (N = 1), CCND1 (N = 1), PAK1 (N = 1), STAU3 (N = 1), RAD51 (N = 1), CD44 (N = 1), NCOR1 (N = 1), RBPMS (N = 1), and WHSC1L1 (N = 1). Pancreas cancers were KRAS wild-type and lung cancers had no co-occurring alterations in ALK, ROS1, EGFR, RET, MET, RAS, or RAF. All tumors were microsatellite stable. A durable response was achieved with anti-HER3 antibody therapy (GSK2849330) in a patient with a CD74-NRG1-rearranged invasive mucinous adenocarcinoma (previously reported). Four patients treated with an irreversible small molecule HER2 inhibitor (afatinib) did not respond to treatment, suggesting direct targeting of HER3 may be superior to HER2 inhibition in patients with NRG1 fusion-positive tumors. Conclusions:NRG1 fusions occur in several tumor types and may be amenable to targeting with HER3-directed therapy.