OBJECTIVE To compare raltitrexed (Tomudex; Zeneca Pharmaceuticals Ltd, Macclesfield, United Kingdom) a direct, specific thymidylate synthase (TS) inhibitor with fluorouracil (5-FU) plus high-dose leucovorin (LV) as first-line treatment for advanced colorectal cancer (ACC). METHODS A total of 495 patients were randomized to raltitrexed (3 mg/m2) once every 3 weeks or 5-FU (400 mg/m2) plus LV (200 mg/m2) daily for 5 days every 4 weeks. RESULTS The randomized groups were well balanced demographically. With a minimum 17-month follow-up, median survival was comparable between groups (10.9 months raltitrexed v 12.3 months 5-FU/LV; hazards ratio, 1.15; 95% confidence interval [CI], 0.93 to 1.42; P=.197), although time to progression was statistically significantly shorter in the raltitrexed group. Overall objective responses were comparable (19% raltitrexed v 18% 5-FU/LV), with more than 50% of patients in each group having stable disease. Significantly less World Health Organization (WHO) grade 3 and 4 stomatitis (2% v 16%, P < .001) and a reduced incidence of leukopenia (6% v 13%) and diarrhea (10% v 19%) occurred in the raltitrexed group (particularly at cycle 1 ). This resulted in fewer dose reductions at cycle 2 (4% raltitrexed v 28% 5-FU/LV) and early quality-of-life (QoL) benefits for raltitrexed patients. Reversible, clinically insignificant increases in transaminases were reported in 13% of raltitrexed patients. Palliative benefits of weight gain, improved performance status, and reduced disease-related symptoms were evident in both groups. CONCLUSIONS Raltitrexed is confirmed as an effective option in the first-line palliative management of ACC, with comparable efficacy to and tolerability advantages (in terms of reduced incidence of stomatitis, diarrhea, and leukopenia) over 5-FU/LV. Raltitrexed has the added convenience of an every 3 weeks dosing schedule.