The ultimate goal of treatment of osteonecrosis (ON) of the hip is preservation of the femoral head and avoidance of total hip replacement. Given limitations in the currently available armamentarium for treatment of ON, in a prospective pilot study our hypothesis was that enoxaparin (60 mg/day, 12 weeks) would prevent progression of stage I-II hip ON associated with thrombophilia-hypofibrinolysis over ≥ 108 weeks follow-up versus untreated historical controls, with different treatment responses in primary versus corticosteroid-associated secondary ON. Patients were selected by ≥ 1 thrombophilia-hypofibrinolysis and Ficat stages I-II ON of ≥ 1 hip(s). A blinded committee interpreted AP and frog-leg lateral x-rays at entry and every 36 weeks to ≥ 108 weeks. Stage I-II maintenance versus progression to stages III-IV-total hip replacement was the major outcome. Sixteen patients had primary ON (25 hips; 13 stage I, 12 stage II), 12 secondary ON (15 hips; 5 stage I, 10 stage II). With no enoxaparin-related complications, 19/20 hips (95%) in primary ON were unchanged from stages I-II at ≥ 108 weeks; 12 of 15 hips (80%) progressed to stages III-IV in secondary ON. In primary ON at ≥ 108 weeks, survival of 95% hips, or 76% (19/25 hips, based on intent to treat), compares favorably with untreated historical controls (˜ 20% 2 year survival), comparable to 20% hip survival in secondary hip ON. Enoxaparin may prevent progression of primary hip ON, preserving the head of the femur, thus reducing the need for total hip replacement.