Most patients with follicular lymphoma experience multiple relapses necessitating subsequent lines of therapy. Ibrutinib, a Bruton tyrosine kinase inhibitor approved for the treatment of several B-cell malignancies, showed promising activity in follicular lymphoma in a Phase 1 study. We report the results of a Phase 2 trial evaluating ibrutinib in recurrent follicular lymphoma. Forty patients with recurrent follicular lymphoma were treated with ibrutinib, 560 mg/day until progression or intolerance. The primary endpoint was overall response rate. Exploratory analyses included correlations of outcome with recurrent mutations identified in a cancer gene panel using next-generation sequencing in pretreatment biopsies from 31 patients and results of early interim PET/CT scans in 20 patients. Overall response rate was 37.5% with complete response rate of 12.5%, median progression free survival (PFS) 14 months and 2-year PFS 20.4%. Response rates were significantly higher among patients whose disease was sensitive to rituximab (52.6%) compared to those who were rituximab refractory (16.7%) (p=0.04). CARD11 mutations were present in 16% (5/31) of patients and predicted resistance to ibrutinib with only wild-type patients responding (p=0.002). SUVmax at cycle 1 day 8 correlated with response and PFS. Ibrutinib was well-tolerated with a toxicity profile similar to labeled indications. Ibrutinib is a well-tolerated treatment with modest activity in relapsed follicular lymphoma. Evaluation of BTK inhibitors in earlier lines of therapy may be warranted based on improved response rates in rituximab sensitive disease. Somatic mutations such as CARD11 may impact response to ibrutinib and inform clinical decisions and should be evaluated in larger data sets. This trial was registered at www.clinicaltrials.gov as #NCT01849263.