Standard adjuvant chemotherapy for colorectal cancer consists of 5-fluorouracil with leucovorin or levamisole. The large, multicenter, randomized, double-blind QUASAR (Quick and Simple and Reliable) trial investigated whether treatment with a higher dose of leucovorin or the addition of levamisole to 5-fluorouracil and leucovorin improved survival. In the QUASAR study, 4,927 patients with colorectal cancer with no evidence of residual disease following resection, were randomized to receive fluorouracil (370 mg/m2) with high-dose (175 mg) or low-dose (25 mg) leucovorin and either levamisole (50 mg) or placebo. The fluorouracil and leucovorin regimen was given either monthly (as six 5-day courses with 4 weeks between the start of each course) or weekly (as 30 once-weekly doses). Levamisole or placebo was given three times daily for 3 days, repeated every 2 weeks for 12 courses. The primary endpoint was death from any cause. Survival was similar with both high- and low-dose leucovorin (70.1% v 71.0% at 3 years; P = .43) as well as recurrence rates (36.0% v 35.8%; P = .94), and with levamisole compared with placebo (69.4% v 71.5%; P = .06) as well as recurrence rates (37.0% v 34.9%; P = .16). Monthly and weekly treatments were equally effective (although this was a nonrandomized comparison), while weekly treatment was associated with significantly fewer toxic effects (neutropenia, mucositis, and diarrhea). High-dose leucovorin was not associated with a survival or recurrence benefit when compared with low-dose leucovorin. The ongoing QUASAR-1 trial aims to establish whether adjuvant chemotherapy has any worthwhile survival benefit in colorectal cancer patients with an uncertain indication following surgical resection.