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Importance Deep vein thrombosis (DVT) isolated to the calf veins (distal to the popliteal vein) is frequently detected with duplex ultrasonography and may result in proximal thrombosis or pulmonary embolism (PE). Objective To evaluate whether therapeutic anticoagulation is associated with a decreased risk for proximal DVT or PE after diagnosis of an isolated calf DVT. Design, Setting, and Participants All adult patients with ultrasonographic detection of an isolated calf DVT from January 1, 2010, to December 31, 2013, at the Vascular Laboratory of the University of California, Davis, Medical Center were included. Patients already receiving therapeutic anticoagulation and those with a chronic calf DVT, a contraindication to anticoagulation, prior venous thromboembolism within 180 days, or diagnosis of a PE suspected at the time of calf DVT diagnosis were excluded. Data were analyzed from August 18, 2015, to February 14, 2016. Exposures Intention to administer therapeutic anticoagulation. Main Outcomes and Measures Proximal DVT or PE within 180 days of the diagnosis of the isolated calf DVT. Results From 14 056 lower-extremity venous duplex studies, we identified 697 patients with an isolated calf DVT and excluded 313 of these. The remaining 384 patients were available for analysis (222 men [57.8%]; 162 women [42.2%]; mean [SD] age, 60 [16] years). The calf DVT involved an axial vein (anterior tibial, posterior tibial, or peroneal) in 243 patients (63.2%) and a muscular branch (soleus or gastrocnemius) in 215 (56.0%). Physicians attempted to administer therapeutic anticoagulation in 243 patients (63.3%), leaving 141 control participants. Proximal DVT occurred in 7 controls (5.0%) and 4 anticoagulation recipients (1.6%); PE, in 6 controls (4.3%) and 4 anticoagulation recipients (1.6%). Therapeutic anticoagulation was associated with a decreased risk for proximal DVT or PE at 180 days (odds ratio [OR], 0.34; 95% CI, 0.14-0.83) but an increased risk for bleeding (OR, 4.35; 95% CI, 1.27-14.9), findings that persisted after adjustment for confounding factors (ORs, 0.33 [95% CI, 0.12-0.87] and 4.87 [95% CI, 1.37-17.3], respectively) and sensitivity analyses. Conclusions and Relevance Rates of proximal DVT or PE are low after isolated calf DVT. Therapeutic anticoagulation is associated with a reduction of these outcomes but an increase in bleeding.