The interaction among signaling networks of tumor and neighboring stroma cells in complex disease traits is poorly understood, and read-out parameters reflecting tumor-associated functional stages are scarce. A multi-centre phase II trial was designed to prove the hypothesis whether activation of presumably complementary receptor-triggered transcriptional cascades (via pioglitazone and interferon-a) could result in synergistic clinical effects. Therapy consisted of low-dose capecitabine 1 g/m2twice daily po for 14 days, every 3 weeks, day 1+, and etoricoxib 60 mg daily plus pioglitazone 60 mg daily, day 1+, and low-dose interferon-a 4.5 MU sc three times a week, week 1+, until disease progression. Fourty-five patients with renal clear cell carcinoma at a progressive disease stage and ECOG 0–2 were enrolled between March 2003 and April 2008. Forty-two percent of the patients had been systemically pretreated. Objective response was observed in 35% of the patients (PR 27%, CR 9%), which was paralleled by strong CRP decline after 4–6 weeks’ treatment. CRP values decreased from mean 42.3 mg/L, range 9.1–236, to 11.1 mg/L, range 1.1–35.6, P = 0.006. Stable disease >3 months occurred in 40%. Median overall survival and progression-free survival for the total cohort were 26.9 and 7.2 months, for CRP non-responder 13.8 and 2.6 months (95% CI, 6.5–21.1 / 0.4–4.8), and 24.4 and 11.3 months (95% CI, 22.8–31.0 / 5.7–16.9) for CRP responder, P = 0.082 / 0.017 (median observation time 26.1 months). Overall survival at 5 years was 18%. Toxicity >WHO grade 3 was reported: Hand-foot syndrome in 16 patients (36%), diarrhea in 4 patients (9%), depression in 1 patient, and pneumonia in 2 patients. (1) Clinical results of combined anti-inflammatory and angiostatic therapy were comparable with available standard therapies, although 50% of the patients had been systemically pretreated. (2) Control of tumor-associated inflammation is an important therapeutic principle in metastatic renal clear cell carcinoma.