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There are no data from prospective studies concerning the treatment of isolated calf muscle vein thrombosis (soleal and gastrocnemial muscle veins), found in 20–40% of patients with lower extremity thrombosis of the calf. We investigated the outcome in two cohorts of consecutive patients, the first receiving low-molecular-weight heparin for 10 days at therapeutic doses and compression therapy; the second cohort, compression therapy alone. In patients on therapeutic heparin (n = 52), no progression to deep vein thrombosis occurred [0%; 95% confidence interval (CI), 0–6.8%]. Patients without anticoagulation (n = 32) showed a statistically significant higher percentage of progression into the deep calf veins (25%; 95% CI, 11.5–43.4%) as well as recurrent muscle vein thrombosis. No symptomatic pulmonary embolism or bleeding event occurred; one patient died in each group, both related to malignancy. The data suggest a need for short-term anticoagulation in such patients to prevent further thromboembolic complications. Randomized prospective studies are now warranted in a larger study population.