Background The molecular mechanisms underlying colon cancer development are multifactorial. There is a clinical need for better markers than current TNM stages for stratifying risk of recurrent disease and to guide clinicians in choice of adjuvant treatment. The objective of this study is to evaluate the level of differences between recurrent and non-recurrent colon cancer in five year follow-up by proteomics. We identified 4,805 proteins quantified across all ten groups with at least one unique peptide sequence and 1% FDR. For the cluster analysis, 2919 proteins (61%) appear in two clusters differentiating the tumor and control samples. 54 proteins (1 %) appear in a cluster seemingly differentiating recurrent and non-recurrent cancer. A cut-off strategy with pathway analysis identify 255 proteins (5%) different between recurrent and non-recurrent cancer for the combined TNM2 and TNM3 group. Likewise, we identified 727 proteins (15%) for the TNM2 r+/r- group and 343 proteins (7%) for TNM3 r+/r-, partly with overlapping predicted gene findings. We demonstrate the degree of dissimilarity between recurrent and nonrecurrent cancer in a proteomics dataset. We believe these findings are usable for setting up larger scale experiments in recurrent cancer although the study is underpowered for diagnostic purposes.