Background: Randomized trials have shown a lower efficacy of postoperative chemotherapy in rectal cancer patients having received preoperative radiotherapy than in nonirradiated colorectal cancer (CRC) patients. We hypothesized that preoperative radio(chemo)therapy impairs the relative dose intensity (RDI) of further chemotherapy because of long-term radiation damage. This retrospective study aimed to test this hypothesis. Methods: The analysis was conducted on 220 consecutive patients with CRC who received FOLFOX-4 postoperatively or because of cancer relapse. Of these, 41 patients with rectal cancer had preoperatively received radio(chemo)therapy (study group) and the remaining 179 with CRC had not (control group). The RDI of oxaliplatin at 8 and 16 weeks was calculated. Results: The median RDI of oxaliplatin at 8 weeks was 95.91% in the study group and 96.15% in the control group (p = 0.79). The corresponding percentages at 16 weeks were 87.6 and 86.5%, respectively (p = 0.55). It was found that within 0–8 weeks, 26.9% of the patients in the study group and 26.3% in the control group had grade 3+ toxicity, hypersensitivity reactions, or granulocyte colony-stimulating factor administration (p = 0.94). The corresponding percentages for 0–16 weeks were 44.8 and 43.9%, respectively (p = 0.92). Conclusions: We found no association between preoperative radio(chemo)therapy and the RDI of FOLFOX-4. We failed to explain the inferior efficacy of postoperative chemotherapy in patients with rectal cancer who had preoperatively received irradiation compared to those with CRC who had not.