OBJECTIVES: Colorectal cancer is the second most common cancer in Spain (25,600 incident cases and over 13,500 deaths yearly). Mutations in the KRAS oncogene are associated with a poor response to Epidermal Growth Factor Receptor (EGFR) inhibitor therapy in metastatic colorectal cancer (mCRC). In addition to avoiding unnecessary toxicity, implementing routine KRAS screening and limiting the use of EGFR inhibitors to patients with wild-type KRAS may lead to cost savings. The objective is to estimate health and economic outcomes derived from carrying out KRAS determination in mCRC patients requiring an aggressive treatment in Spain. METHODS: Cost-effectiveness and budget impact analyses from national, regional and hospital perspectives were developed in an interactive mode. Information was obtained from literature review of clinical trials (treatment response rates and prevalence of KRAS mutations), official statistics (epidemiological data) and local databases (therapy and KRAS test costs). Multivariate sensitivity analysis can be performed by changing the technology for KRAS testing (PCR, real-time PCR), the chemotherapy regime (FOLFIRI, FOLFOX-4) and the proportion of wild-type patients to be treated with each therapy (bevacizumab, cetuximab). RESULTS: About 7000 mCRC patients will require an aggressive treatment in Spain in 2010. A strategy based on treating wild-type patients with cetuximab would raise first line response rate from 44.80% to 53.84% (20.18%, 633 patients more) when combined with FOLFIRI (19.05%, 620 patients with FOLFOX-4) with an additional cost estimate of €22,117 per response (€17,201 with FOLFOX-4). Budget impact of this approach amounts to a 9.06% (5.01% with FOLFOX-4) increase in resources devoted to mCRC treatment. Univariate and multivariate sensitivity analyses yield ratios between €19,101 and €27,531 and budget impact estimates of 0.16-9.16%. CONCLUSIONS: Treating wild-type KRAS mCRC patients with cetuximab would lead to over 600 additional patients (19-20%) with first line response every year in Spain, with an associated budget impact of 9-11% of therapy cost.