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 with that in mucosa from subjects posttumor removal. Six postabsorptive patients with localized rectal cancer and five postsurgical 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 h. Protein synthesis was calculated from protein-bound leucine enrichment (determined by capillary GC-combustion IRMS) and from the enrichment of free intracellular leucine (determined by GC-quadrupole MS). 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). These findings do not support the concept that colorectal cancer originates from a proliferative disease of the whole colon. Increased mucosal protein synthesis appears to depend on the presence of the tumor itself and should therefore be considered a secondary phenomenon.