The aim of this study was to investigate the dynamic changes of circulating tumor cells (CTCs) in patients with hepatocellular carcinoma (HCC) before and immediately after conducting a microwave ablation (MWA) and conventional transarterial chemoembolization (C-TACE). Additionally, the CTCs short-term dynamics were compared with the clinical course of the HCC-patients. Blood samples from 17 patients with HCC who underwent MWA (n = 10) or C-TACE (n = 7) were analyzed. Venous blood was taken before and immediately after the radiological interventions to isolate and quantify CTCs using flow cytometry. CTCs were identified as CD45- and positive for the markers ASGPR, CD146 and CD274 (PD-L1). Patients were followed of up to 2.2 years after the radiological intervention. CTCs were detected in 13 HCC patients (76%) prior to the radiological interventions. The rate of CTCs was significantly decreased after the intervention in patients treated with MWA (0.4 CTCs/mL of blood, p = 0.031). However, no significant differences were observed in patients who received C-TACE (0.3 CTCs/mL of blood, p = 0.300). Overall, no correlation was found between the CTCs rate before and after the radiological intervention and recurrence rate of HCC. This preliminary data could confirm the tumoricidal effects of MWA in patients with HCC by significantly decreasing CTCs rate. In our study, we were able to detect CTCs in HCC patients using 3 different tumor markers. This preliminary data shows significant lower CTCs detected in response to MWA. However, large-scale randomized clinical trials are needed to determine the future role and the prognostic relevance of CTCs following this treatment.