In a porcine tibia model, we subjected widely used anchor-suture combinations to a fatigue-testing protocol. The Ethibond No. 2 suture was the weakest part of the anchor-suture combinations when they were loaded to failure by a single pull. Under cyclic-loading conditions, fixation strength was decreased compared with single-pull tests. The suture/anchor interface was identified as the weakest link in the Mitek GII/No. 2 combination and in the Zimmer Statak 3.5/No. 2 combination. In most cases the suture was worn through at the eyelet. Threading the Gll anchor with a No. 5 suture and use of larger anchors in combination with No. 2 sutures increased the fatigue strength. Suture breakage at the knot was the predominant failure mode for biodegradable anchors inserted into cortical bone. The highest fatigue strength was seen for the Super Anchor/No. 5 combination when the anchor was inserted in cortical bone. Fatigue testing is crucial for evaluation of suture anchors and should be performed along with single-pull testing. The mechanical performance of a suture anchor threaded with a defined suture depends on several key factors: the pullout strength of the anchor, the tensile strength of the suture, and the interaction of anchor and suture at the eyelet (suture/anchor interface).