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Accurate identification of factors associated with progression of colorectal cancer remains a challenge. In particular, it is unclear which statistical methods are most suitable to separate the effects of putative prognostic factors on cancer progression vs cancer-specific and other cause mortality. To address these challenges, we analyzed 10 year follow-up data for patients who underwent curative surgery for colorectal cancer in 1985–2000. Separate analyses were performed in two French cancer registries. Results of three multivariable models were compared: Cox model with recurrence as a time-dependent variable, and two multi-state models, which separated prognostic factor effects on recurrence vs death, with or without recurrence. Conventional multi-state model analyzed all-cause mortality while new relative survival multi-state model focused on cancer-specific mortality. Among the 2517 and 2677 patients in the two registries, about 50% died without a recurrence, and 28% had a recurrence, of whom almost 90% died. In both multi-state models men had significantly increased risk of cancer recurrence in both registries (HR = 0.79; 95% CI: 0.68–0.92 and HR = 0.83; 95% CI: 0.71–0.96). However, the two multi-state models identified different prognostic factors for mortality without recurrence. In contrast to the conventional model, in the relative survival analyses gender had no independent association with cancer-specific mortality whereas patients diagnosed with stage III cancer had significantly higher risks in both registries (HR = 1.67; 95% CI: 1.27–2.22 and HR = 2.38; 95% CI: 1.29–3.27). In conclusion, relative survival multi-state model revealed that different factors may be associated with cancer recurrence vs cancer-specific mortality either after or without a recurrence.