Patients treated on a Phase-I clinical trial of photodynamic therapy (PDT) developed a systemic capillary leak syndrome that constituted the dose-limiting toxicity. We examined serum samples from patients treated at the maximally tolerated dose level for evidence of a systemic, cytokine-mediated inflammatory response. Patients underwent pleurectomy or extrapleural pneumonectomy (EPP) followed by intraoperative PDT of the thorax using Foscan® at a dose of 0.1 mg/kg 6 days before surgery and 652 nm red light at a dose of 10 J/cm². Levels of interferon-γ (IFN-γ), tumor necrosis factor–α (TNF-α), interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-12 were assayed before Foscan® administration; after anesthetic induction, surgical resection and light delivery; in postoperative recovery and the day after the surgery. Of the analyzed patients, eight underwent a pleurectomy and one an EPP followed by PDT. IFN-γ, TNF-α and IL-12 showed no elevation, but IL-1β, IL-6, IL-8 and IL-10 levels were elevated after surgery and PDT. IL-1β showed a statistically significant variation from baseline after surgery and IL-6, after PDT. The results suggest a systemically mediated inflammatory response resulting from thoracic surgery followed by PDT. Further investigation of specific mechanisms is warranted.