Background: Salivary gland cancers (SGC) are rare, biologically and histologically diverse malignancies with no standard of care therapy in the recurrent/metastatic setting. Eribulin is a microtubule inhibitor with established efficacy in previously treated breast cancer. The purpose of this study was to determine the anticancer activity of eribulin in advanced SGC. Methods: In a single center two-stage single arm phase II design, patients with progressive, recurrent and/or metastatic SCG of the head and neck or other sites, with documented disease progression within the past 6 months and not amenable to curative intent therapy were eligible. Any number of prior cytotoxic chemotherapies was allowed. Patients received eribulin 1.4 mg/m2 IV on Days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicities. Response was assessed by CT imaging every 6 weeks. The primary endpoint was overall response rate by RECIST 1.1. Secondary endpoints were duration of response (DOR), progression free survival (PFS), disease control rate (DCR), and grade > = 3 toxicities. Results: Between May 2012 and August 2015, 29 patients were enrolled. Median age was 63 (range 34-75); 20 (69%) were male. The most common histologies were adenoid cystic (n = 10) and adenocarcinoma (n = 5). Prior radiation was administered in 25 (86%). Number of prior cytotoxic therapies were: 0 (12, 41%), 1 (13, 45%), 3(3, 10%), 5 (1, 3%). Neutropenia was the most common toxicity (Grade 3 (9, 31%), Grade 4 (4, 14%)). Other grade 3 toxicities were: febrile neutropenia, increased QTc, fatigue and peripheral neuropathy in a single patient each. Median follow-up is 2 years, with 5 patients continuing on treatment. The median number of cycles administered was 4 (range 2-28). Response by RECIST criteria was observed in 3/29 (10%) with 2 PR and 1 CR , 20/29 (69%) patients demonstrated a decrement in tumor size at first assessment. Median PFS was 3 months, DCR was 26/29 (90%) and median DOR was 17.2 months. Conclusions: In this phase II trial of eribulin for advanced SGC, we observed response rates similar to those reported to other cytotoxic therapies and superior to those observed in trials of TKIs. Toxicities were similar to those observed in prior trials with eribulin. Clinical trial information: NCT01613768