Although recent trials have raised concerns about the toxicity of raltitrexed monotherapy in patients with advanced colorectal cancer (aCRC), similar concerns have also been raised with other chemotherapy regimens in aCRC. The lessons learnt form our previous experiences with raltitrexed are, therefore, still important as they offer practical guidances to optimise tolerability of chemotherapy for CRC in general. The aims of the study were to report the low-toxicity profile in 58 patients receiving raltitrexed when a rigorous patient information and education strategy was implemented together with an intensive supportive adjuvant drugs regimen from the start. After a discussion with the consultant, all patients received a further consultation with a specialist nurse, a series of bespoke information tools, including an information video and written guidelines on how to avoid, prevent and deal promptly with the side-effects of raltitrexed. They all received intravenous adjuvant ondansetron and dexamethasone, then oral domperidone, ranitidine and nystatin from cycle one. The dose intensity was 98% over 307 cycles. Toxicity associated with raltitrexed comprised grade 1/2 diarrhoea (31.6% of treatment cycles), nausea (12.4%) and vomiting (8.4%), with no grade 3/4 events; grade 1/2 alopecia (17.9%); grade 1 (only) stomatitis (2.3%) and grade 1/2/3 lethargy (70.3%, only 2.3% grade 3), anaemia (14.3%, only 0.3% grade 3) and neutropenia (3.3%, only 0.3% grade 3). There were no treatment-related deaths. The low toxicity, despite high-dose intensity, suggests that intensive supportive education and drugs should have a role in the future design of regimens containing raltitrexed and other chemotherapy regimens for colorectal carcinoma.