OBJECTIVE To evaluate the influence of pentoxifylline (PTX), a phosphodiesterase inhibitor, on cytokines and inflammatory proteins in patients suffering from septic shock. METHODS Prospective study comparing a therapy group to a matched control group. METHODS Medical intensive care unit at a university hospital. METHODS Twenty four patients fulfilling the criteria of septic shock were included in this study. Twelve patients received PTX (therapy group) and 12 patients matched for diagnosis, age and gender served as the control group. METHODS Pentoxifylline at 1 mg/kg per hour over 24 h in the therapy group. RESULTS Cytokine levels [tumor necrosis factor-alpha (TNF)], soluble TNF receptor [TNF-R], and interleukin-6 [IL-6] and inflammatory proteins [C-reactive protein, alpha-1-antitrypsin (AAT), fibronectin, and haptoglobin], as well as hemodynamic parameters and the APACHE III score were evaluated before initiation of therapy and 24 h-later. After 24 h, TNF levels were significantly lower in the therapy group (p = 0.013), while IL-6 levels were significantly higher in the therapy group (p = 0.030). Within the 24 h TNF declined significantly in the therapy group (p = 0.006), while IL-6 showed a significant increase (p = 0.043). AAT and the APACHE III score tended to differ significantly after 24 h between the groups [AAT levels higher in the therapy group (p = 0.05), APACHE III score lower (p = 0.05)]. In the therapy group, the systemic vascular resistance index was significantly higher after 24 h (p = 0.0026) whereas the cardiac index declined (p = 0.035). CONCLUSIONS PTX does influence TNF levels in septic shock patients. Nevertheless, inhibiting a single mediator in severe septic shock cannot stop the inflammatory overreaction.