Isolated distal deep vein thrombosis (DVT), also known as calf DVT, represents up to 50% of all lower limb DVT in ultrasound series and is therefore a frequent medical condition. Unlike proximal DVT and pulmonary embolism (PE), which have been extensively studied and for which management is well standardized, much less is known on the optimal management of isolated calf DVT. Data arising from registries and non-randomized studies suggest that most distal DVTs do not extend to the proximal veins and have an uneventful follow-up when left untreated. These data had some impact on some international recommendations like the American College of Chest Physicians (ACCP), which recently stated that ultrasound surveillance instead of systematic therapeutic anticoagulation might be an option for selected low-risk patients. However, robust data arising from randomized studies are scarce. Indeed, only six randomized trials assessing the need for anticoagulation for calf DVT have been published. Many of these trials had an open-label design and were affected by methodological limitations. When considering randomized placebo-controlled trials, one included low-risk patients (outpatients without cancer or previous venous thromboembolic events [VTE]) and was hampered by a limited statistical power (CACTUS study). Nevertheless, data from this trial tend to confirm that the use of therapeutic anticoagulation in low-risk patients with symptomatic calf DVT is not superior to placebo in reducing VTE, but is associated with a significantly higher risk of bleeding. The most recent randomized placebo-controlled trial did not assess the necessity of anticoagulant treatment but rather the long-term risk of recurrence and the duration of treatment and compared 6 weeks vs 12 weeks of treatment with rivaroxaban (RIDTS study). Overall, available data suggest that the use of therapeutic anticoagulation in low-risk patients with symptomatic calf DVT is not superior to placebo in reducing VTE. High risk patients (previous VTE, active cancer, inpatients) might benefit from a course of anticoagulant treatment. However, the optimal anticoagulant intensity and duration are uncertain. It might well be possible that after an initial short therapeutic anticoagulation period, a prophylactic anticoagulation might be enough to avoid recurrences and to decrease the bleeding risk. This will be the principal research question of the upcoming API-CALF study (Apixaban to treat calf vein thrombosis study, NCT 04981327). After receiving a therapeutic apixaban dose during 7 days, patients will be randomly assigned to apixaban 5 mg twice daily (therapeutic dose) or to apixaban 2.5 mg twice daily (prophylactic dose) during three months. Hopefully, this will help guiding physicians to prescribe the treatment associated with the best benefit-risk ratio in the next future.