The therapeutic regimen option for the cancer-associated thrombosis (CAT) patients is still a major clinical challenge. The present study aimed to investigate the safety and efficacy of pharmacomechanical catheter-directed thrombolysis (PCDT) with AngioJet treatment compared with the conventional anticoagulation alone therapy in the patients with CAT. We retrospectively reviewed the patients who underwent PCDT and/or anticoagulation for the treatment of CAT between August 1, 2016 and March 1, 2022. Each patient was divided into the PCDT group or the anticoagulation alone group. The baseline demographics, comorbidities, clinical characteristics, treatment details, course data were reviewed. A total of 51 eligible patients were included, of whom 21 were in PCDT group (mean age, 60.1 ± 13.0 years; 52.4% male) and 30 in anticoagulation alone group (mean age, 66.6 ± 11.1 years; 50.0% male). No significant differences regarding age, sex, onset time, limb characteristics, cancer conditions or risk factors were detected (p > .05). After PCDT, grade III lysis was achieved in 8 and grade II lysis in 11 patients. Clinical success was achieved in 90.5% (19/21) patients. The symptoms of leg pain and swelling were significantly improved in both groups. Except for transient macroscopic hemoglobinuria occurring in PCDT group, none of all patients suffered from procedure-related and major complications. Minor complications such as bleeding events occurred in 23.8% (5/21) of patients in PCDT group compared with 10.0% (3/30) in anticoagulation alone group (p > .05). At the 6-month follow-up, iliofemoral patency was found an absolute risk reduction of 37.9% (70.0 vs. 32.1%) (95% CI: 1.183-4.008%; P = 0.010). The incidence of mild PTS was 5.0% (1/20) in PCDT group compared with 10.7% (3/28) in anticoagulation alone group (p > .05). The PCDT is a safe and effective modality in managing patients with CAT, leading to improved clinical outcomes with a low complication. The PCDT was more effective than anticoagulation alone in massive symptom relief and venous patency.