Background: Vascular pythiosis, caused by Pythium insidiosum, is a life-threatening disease with high mortality rate in patients with residual disease post-surgery. This study evaluated the effectiveness of a combination therapy of surgery, azithromycin, doxycycline, and itraconazole. Methods: In this open-label, Phase II multicenter trial, 51 patients were enrolled. Patients were categorized based on residual disease post-surgery (unresectable lesions, incomplete resection, or persistent symptoms). Patients with residual disease received azithromycin (500 mg daily), doxycycline (100 mg twice daily), and itraconazole (200 mg thrice daily) until beta-d-glucan (BDG) levels were negative (<80 pg/mL) for 3 months. Those without residual disease received the same regimen for 6 months. Outcomes included all-cause mortality at 6 months, adverse events, changes in BDG levels over time, and factors associated with residual disease and mortality. Results: At 6 months, the all-cause mortality rate was 15.7%. Mortality in patients with residual disease was 31.5% compared to 6.25% for those without (P = .04). Lesions above the popliteal artery were a significant predictor of residual disease (incidence rate ratio [IRR] 3.20, 95% confidence interval [CI]: 1.08–11.70). BDG levels decreased over time (odds ratio [OR] 0.82, 95% CI: .77–.88 per week, P < .001) but remained higher in the residual disease group (OR 4.29, 95% CI: 1.55–11.92) Conclusions: The combination therapy of surgery, azithromycin, doxycycline, and itraconazole improves survival in patients with vascular pythiosis, including those with residual disease. This regimen is well tolerated and should be considered a standard of care, with further research needed for long-term outcomes.