Radiofrequency thermal ablation (RFTA) is a local tumor-destructing technique that can potentially modulate the host immune response through mechanisms that are not clearly defined. We assessed whether RFTA could affect multiple systemic inflammatory and immunological parameters, including CD25+Foxp+ cells, in patients with primary or metastatic lung tumors. Three days after RFTA, a moderate and temporary systemic inflammatory response developed, as demonstrated by the increase in peripheral neutrophils and monocytes and in plasma levels of proinflammatory chemokines (MIP-1alpha, MIP-1beta, eotaxin, and interleukin[IL]-8) and acute phase reactants (complement C3 and C4, serum amyloid, alpha1 antichymotrypsin, and C-reactive protein). Moreover, we found a concomitant release of the anti-inflammatory factor IL-10. Thirty days after RFTA, a significant reduction in CD25+Foxp3+ counts with an increase in CD4+ T-cell proliferation and number of interferon-gamma-secreting cells was observed. The reduction in CD25+Foxp3+ cells lasted up to 90 days after treatment. The use of RFTA in lung cancer patients has an immunomodulatory activity: it induces a self-limiting systemic inflammation early and later a reduction of circulating CD25+Foxp3+ Tregs. In addition to tumor ablation, downmodulation of this regulatory subset might be an important mechanism involved in the long-term clinical efficacy of RFTA.