Unfractionated heparin has been the standard anticoagulant used immediately after mechanical heart valve replacement (MHVR). The purpose of this study was to assess a postoperative anticoagulation protocol with low-molecular-weight heparin (LMWH) immediately after MHVR without the use of unfractionated heparin or anti-factor Xa monitoring. We performed a prospective, single-center, observational study of 1,063 consecutive patients undergoing elective MHVR with postoperative LMWH anticoagulation treatment. The exclusion criteria were as follows: renal failure, intraaortic balloon counterpulsation, critical perioperative state, or a recent neurologic event. The postoperative anticoagulation protocol used subcutaneous enoxaparin as a bridging anticoagulant treatment beginning on the first postoperative day and continuing until vitamin K antagonist treatment was fully effective. Patients were followed for 6 weeks. The primary endpoints were the incidence of thromboembolic or major bleeding events. Eleven (1%) thromboembolic events occurred. Ten of these events were transient or permanent strokes. Major bleeding events occurred in 44 patients (4.1%), 7 of which were observed before the enoxaparin treatment period. At the time of discharge, 570 patients (53.6%) were no longer receiving LMWH treatment due to achieving the target international normalized ratio. The mean length of hospital stay was 8.5 ± 2.9 days. There were no deaths during the 6-week follow-up period. In our highly selected population, after MHVR, postoperative anticoagulation using LMWH is associated with a low rate of thromboembolic and major bleeding events. This large observational study demonstrates that the use of LMWH as an anticoagulant is effective and safe after MHVR.