An angiostatic approach was used to assess the impact of anti-inflammatory therapy in combination with metronomic low-dose chemotherapy. A randomized multi-institutional phase II trial was designed to select metronomic chemotherapy (arm A: trofosfamide 50 mg orally three times daily, day 1+) or combined anti-inflammatory/angiostatic treatment (arm B: trofosfamide as above mentioned plus rofecoxib 25 mg orally, day 1+, and pioglitazone 60 mg orally, day 1+) for further evaluation. A total of 76 patients, mostly (>60%) refractory to at least one previous chemotherapy with maximum tolerated doses, and progression of metastatic melanoma were included. The estimated progression-free survival (PFS) rates at one year were 0% for metronomic chemotherapy (A), but 9% for additional anti-inflammatory therapy (B). Vice versa the hazard ratio for the intent-to-treat analysis of A versus B was 1.9 (P=0.008). By Cox analysis, the impact of anti-inflammatory therapy on PFS achieved significance (P=0.016) as well as C-reactive protein response on overall survival (P=0.045). WHO grade 3 (no grade 4) toxicities were reported in arm A/B in 19 and 28%, respectively. In conclusion, control of tumour-associated inflammatory processes (C-reactive protein response) is associated with longer PFS than achieved with metronomic chemotherapy alone in metastatic melanoma.