Ulcerative colitis is a chronic inflammatory bowel disorder of unknown etiology. Treatment of flare-ups is based on mesalamine and steroids. Treatment of moderate to severe ulcerative colitis with high-dose heparin and low-molecular-weight heparin was reported. The mechanism was assumed to be a combination of anti-coagulant and anti-inflammatory effects. Low-molecular-weight heparin is better and safer than unfractionated heparin. Studies of low-dose low-molecular-weight heparin in experimental models of inflammation and in inflammatory diseases demonstrated a beneficial effect. Our aim in this study was to evaluate the effect of low-dose, low-molecular-weight heparin in active ulcerative colitis. Twelve patients with flare-ups of colitis were prospectively enrolled. Subcutaneous injections of 5-mg enoxaparin were administered at weekly intervals for 12 weeks. Mesalamine doses remained unchanged. Clinical, laboratory, endoscopic, histologic, and quality-of-life scores were evaluated at the beginning and end of the study. Ten patients completed the study. Mean age was 40.1; the female–male ratio was 7:3. Mean Mayo scores were 9.0 ± 0.94 at baseline and 3.4 ± 2.0 at the end of the study (P = 0.0001). Endoscopic scores decreased from 2.2 ± 0.4 to 1.2 ± 1.0 (P = 0.049) and in 7 of 10 patients extent of disease shortened. A significant increase in IBDQL scores from 135.7 ± 37.17 to 179.6 ± 45.15 points was demonstrated (P = 0.0117). Adverse events were one hospitalization due to abdominal pain, arthralgia (1), transient peripheral edema (1), and elevation of alkaline phosphatase (1). During follow-up, one patient required colectomy and another experienced an exacerbation. In conclusion, low-dose low-molecular-weight heparin once a week, combined with mesalamine, may be an effective therapy for active ulcerative colitis. It may delay or preclude the need for steroid treatment. Controlled studies to evaluate efficacy are needed.