The objectives of this cadaveric study were 2-fold: to determine the effect of different locking configurations on the cyclical fatigue strength of flexor tendon repairs and to assess the differences between each repair when a 3-0 or 4-0 suture is used. One hundred twenty flexor digitorum profundus tendons were cut and repaired using nonlocked, simple locked, and cross-stitch locked variations of 2- and 4-strand flexor tendon repairs. Using an incremental cyclical loading protocol we performed 10 trials of each repair with both 3-0 and 4-0 sutures and analyzed the number of Newton-cycles to failure using a 3-way ANOVA. The use of a 3-0 suture led to a 2- to 3-fold increase in fatigue strength in all repairs tested and the fatigue strength of the 4-strand repairs was significantly greater than the 2-strand repairs. All repairs performed with 4-0 suture failed by suture rupture. Of the 3-0 suture repairs, the three 2-strand repairs and the 4-strand cross-stitch locked repair failed by suture rupture. In contrast, 6 of 10 of the 4-strand simple locked and nonlocked repairs failed by suture pullout. There was no significant difference in fatigue strength between the 2 locked and the nonlocked 2-strand repairs using either 3-0 or 4-0 suture. There also was no significant difference in holding capacity or fatigue strength between the simple locked or nonlocked 4-strand repairs. However, the 4-strand cross-stitch locked repair with a 3-0 suture had significantly improved fatigue strength and holding capacity compared with the other repairs tested. Based on the consistently inferior biomechanical performance of 4-0 suture, we recommend that 3-0 suture be considered for 2- or 4-strand tendon repairs when early active motion is planned. The orientation of the transverse and longitudinal components of simple locked repairs did not significantly influence their holding capacity or fatigue strength. The cross-stitch type of locked repair provides better holding capacity and fatigue strength compared with simple locked or nonlocked 4-stranded flexor tendon repairs.