In this prospective study, we evaluated the efficacy of using porcine small intestine submucosa (SIS) xenograft to augment the repair of massive rotator cuff tears. Our hypothesis was that SIS xenograft would help restore tendon tissue in the human model, as has been shown in several animal studies. Eleven patients were followed clinically for a mean of 26 months (range, 14-38 months). Mean University of California Los Angeles end-result scores improved from 13.9 before surgery to 25.7 after surgery, American Shoulder and Elbow Surgeons scores improved from 36.3 to 71.8, and the visual analog scale pain score decreased from 6.6 to 2.0. All findings were statistically significant (P<.01). At a mean of 25 months after surgery, magnetic resonance arthrography (MRA) showed the repairs partially or completely intact in 44% of shoulders. Intact repairs were thin and wispy. There were 3 complications, which included 1 infection and 2 localized skin reactions that resolved spontaneously. SIS xenograft did not reconstitute rotator cuff tissue or add to the quality of the rotator cuff repair. Given clinical concerns about localized reactions in this series and suboptimal MRA findings, use of SIS xenograft to augment rotator cuff repairs is not recommended.