Study Objective: To investigate why security of identical knot sequences is variable and how to avoid occasionally insecure knots. Design: A factorial design was used to assess factors affecting the security of half knot (H) and half-hitch (S) knot combinations. The effect of tying forces and the risk factors to transform H knots into S knots were investigated. The risk factors evaluated were as follows: starting with an H1 or H2 instead of an H3 knot, inexperience, short sutures, and monomanual knot tying. Security of transformed knots, S2S1 and S2S2 knots, and their recuperation with 2 additional half hitches, SSb or SbSb, were evaluated. Setting: Training center for laparoscopic suturing. Patients: Not applicable. Interventions: Security of knots was evaluated in vitro. Measurements and Main Results: The forces that caused knot combinations to open before breaking of the suture were used to calculate the risk of opening with low forces. Tying more strongly increased the security of half knots (H2H1sH1s) (p <.02) and half hitches (p <.001). The forces needed to transform an H3 into an S3 are higher than those for an H2 (p <.001), and the risk increases when the surgeon is inexperienced (p <.001), when sutures are short (p <.001), and when monomanual knot tying (p <.001) is used. Inadvertently made S2S1 and S2S2 knots are dangerous, with the exception of the symmetric S2S2, which is stable. Unstable knots such as S2S1a and S2S2a knot combinations improve with 2 additional blocking half hitches (SbSb), but S2S2aSbSb remains occasionally insecure. Conclusion: To reduce the risk of accidentally transforming a first H into an S knot, it is recommended to start with an H3, tie with force, avoid short sutures, and use bimanual suturing. This permits the recommendation to use preferentially H3H2 knots or 5 half hitches (SSSbSbSb). When in doubt, half knot combinations should be secured with at least 2 blocking half hitches.