Background: It is currently controversial whether mucosal hyperproliferation is involved in colorectal cancerogenesis. The purpose of the present study was to examine protein synthetic rate as an indicator of potential tissue proliferation in grossly normal rectal mucosa from cancer-bearing subjects, and to compare this rate to that in mucosa from subjects post tumor removal. Materials and Methods: Six postabsorptive patients with localized rectal cancer and six post-surgical control subjects received a primed-constant infusion of 1-¹³C-leucine (0.16 µmol/kg min, 9.6 µmol/kg prime). Forceps biopsies from the mucosa were taken after 3 and 6 hours. Protein synthesis was calculated from protein-bound leucine enrichment (determined by capillary gas chromatography (GC) / combustion isotope ratio mass spectrometry (IRMS)), and from the enrichment of free, intracellular leucine (determinated by GC/quadrupole MS). Results: In cancer-bearing subjects mucosal protein synthesis amounted to 1.28 ± 0.24 %/h. This rate was significantly higher (p < 0.05) than the corresponding rate of mucosa from patients after cancer removal (0.69 ± 0.09 %/h). Conclusion: These findings do not support the concept that colorectal cancer originates from a proliferative disease of the whole colon. Increased mucosal proliferation appears to depend on the presence of the tumor itself and should, therefore, be considered a secondary phenomenon.