Background: Although theCapeOX (capecitabine+oxaliplatin) regimen obviates the need for a central venous port, administration of oxaliplatin through peripheral vein can cause venous pain. One of the reasons is pH. The pH level of oxaliplatin solution is about 4.8 and that of buffered by steroid is approximately 7.0. To test the hypothesis that adjusting the pH of oxaliplatin solution by mixing steroid can reduce venous pain, we have conducted the randomized control study to compare pH-adjusted oxaliplatin solution with unadjusted oxaliplatin solution. Methods: This was a single-blinded multicenter randomized phase II study. Colorectal cancer patients receiving oxaliplatin through peripheral vein were enrolled and randomly assigned to arm A (oxaliplatin 130 mg/m² with dexamethasone (DEX) 2 mg) or arm B (the same, without DEX) (UMIN000004286. Venous pain was evaluated according to CTCAE criteria (ver. 4.0) and the verbal rating scale (VRS). Assessments were conducted every 3 weeks until cycle 4. Results: A total of 53 patients (38 men and 15 women; median age, 67 y.o.) were enrolled at 9 institutions in Japan. Of these, 47 evaluable patients were randomized to either arm A (n = 24) or arm B (n = 23). The incidence of venous pain (grade ≥ 2) was 33.3% in arm A and 60.9% in arm B (relative risk 0.55; p = 0.082). The venous pain (VRS score ≥ 3) was 12.5% in arm A and 26.1% in arm B (relative risk 0.48; p = 0.286). No difference was observed in response rate and safety. Conclusions: Adjusting the pH of oxaliplatin solution by addition of a low dose of DEX reduced severe venous pain without influence on response rate and safety. Clinical trial information: UMIN000004286.