Metastatic colorectal and other locally advanced gastrointestinal (G.I.) cancers often recur after curative resection. Many mechanisms of tumor growth and/or immune escape by residual cancer cells may provoke tumor progression. Long-term, cytostatic action with repeated post-adjuvant administration of 5-fluorouracil (FU)-leucovorin (LV) cycles may interrupt or downregulate these mechanisms and favor the recovery and/or increase the immune system activity. Seventy patients were considered. An active prospective cohort including 21 patients (study group) was matched in a 1:1 ratio with a retrospective parallel control group of 21 patients. The study group received long-term repeated post-adjuvant administration of 5-FU-LV cycles, while the matched control group was conventionally treated. Statistical analysis was performed by Kaplan-Meier method and Cox's proportional hazard regression model. The five-year disease-free survival (DFS) was 77.0 + 10.1% and 31.7 + 10.6% (p = 0.001; hazard ratio (HR) 5.3, 95 % C.I.: 1.7-16.1, p = 0.003), while the five-year overall survival (OS) was 88.0 + 8.1% and 37.0 + 10.7% (p = 0.001; HR 8.9, 95% C.I.: 2.0-39.9, p = 0.004) in the study group and in matched controls respectively. These findings suggest a relevant improvement in the outcome of this population by an intermittent and prolonged cytostatic effect with 5-FU-LV.