Objectives: The purpose of this study was to evaluate the feasibility, safety, and efficacy of computed tomography (CT)-guided percutaneous microwave ablation (MWA) of liver hepatocellular carcinoma (HCC) lesions in patients with pre-existing diuretic-resistant ascites. There is logical hesitation among clinicians to pursue MWA in these decompensated patients for fear of worsening an already bleak prognosis, but there is limited evidence to justify this behavior. Material and Methods: A retrospective review of HCC treated with percutaneous MWA at a single center was performed. 18 patients who underwent CT-guided MWA with pre-existing diuretic-resistant ascites were identified. A control group of 29 patients who underwent CT-guided MWA without pre-existing diuretic-resistant ascites was identified, which was further narrowed to 18 patients after matching by Model for End-Stage Liver Disease-Sodium score and age. The effectiveness of treatment was compared between the two groups and evaluated by disease-free survival, residual disease, and overall survival over 36 months. Kaplan–Meier curves plotting the survival function were constructed to compare these variables in both groups. Results: MWA was successfully performed in all patients. The probability of survival at 1 year for the ascites and matched control groups were 0.778 and 1.00, respectively (P = 0.038). The probability of survival at 3 years for the ascites and matched control groups were 0.556 and 0.630, respectively (P = 0.237). There were no significant differences between residual disease and disease-free survival between the two groups at 1 or 3 years. Conclusion: CT-guided percutaneous MWA for HCC in select patients with pre-existing diuretic-resistant ascites is a feasible, safe, and effective treatment option.