Background: Adjuvant chemotherapy is recommended for high-risk stage II (pT4) and III (pN+) colon cancer. Reduction of 6 to 3 months adjuvant capecitabine and oxaliplatin (CAPOX) was rapidly adopted in the Dutch guideline in 2017, after the IDEA trial showed no clinically relevant difference in prognosis and lower toxicity. However, practice variations persist especially in high-risk stage III (pT4/N2). Our study aimed to investigate whether real-world overall survival (OS) and patient-reported outcomes (PROMs) differ between 3 and 6 months of CAPOX. Methods: Data from all patients with high-risk stage II and III colon cancer undergoing surgical resection and adjuvant CAPOX in 2015-2019 was requested from the nationwide Netherlands Cancer Registry. Patients receiving 3 months of CAPOX defined as 1-4 cycles in 2018-2019 after the guideline change (n = 2108) were compared to patients receiving 6 months of CAPOX defined as 5-8 cycles in 2018-2019 (n = 204) plus all patients treated in 2015-2016 (n = 2330). OS was analyzed in a multivariable Cox regression model including stage, ASA, age, sex, sidedness, prior malignancy, radicality, number of lymph nodes dissected, lymphatic and vascular invasion, differentiation grade and mismatch repair status. PROMs for chemotherapy-induced peripheral neuropathy (CIPN20, n = 366), quality of life (QLQ-C30, n = 396) and workability (WAI, n = 120) were compared 2 years after completing 3 versus 6 months of CAPOX. Results: Patients receiving 3 versus 6 months of adjuvant CAPOX showed similar baseline characteristics and comparable 3-year OS (both 90%, 95%CI [88-91%], HR 1.02, 95%CI [0.88-1.19]), also in the high-risk stage III subgroup (n = 1816, 3-year OS 81% [78-84%] versus 81% [79-84%], HR 1.04 [0.85-1.26]). Patients receiving 3 months of CAPOX reported lower long-term CIPN scores compared to 6 months (scale 0-100, mean 16.5 SE [0.5] versus 26.2 [1.0], p < 0.001) and were less likely to experience persistent tingling, burning pain, numbness, difficulty in walking and in manipulating small objects. In addition, the quality of life summary score was higher (scale 0-100, 83.9 [0.5] versus 80.9 [1.1], p = 0.013), most predominantly better role and social functioning, and less fatigue, nausea and appetite loss. Self-assessed workability was better following 3 versus 6 months of CAPOX (scale 1-10, 7.6 [0.3] versus 6.6 [0.5], p = 0.042), with a good or excellent total WAI score (≥37 on scale 7-49) in 50.3% versus 44.8% of patients (p = 0.25). Conclusions: This large population-based cohort of high-risk stage II and III colon cancer patients confirmed that the IDEA-based guideline change from 6 to 3 months of adjuvant CAPOX provided no disadvantage in OS, also for the high-risk stage III patients, and showed an advantage in neurotoxicity, quality of life and workability. These findings support 3 months of adjuvant CAPOX in daily clinical practice.