Simple SummaryDepression is a common disorder in cancer patients. In this population-based prospective cohort study, we investigated if patients with colorectal cancer experience a higher risk of pharmacological or hospital treatment for depression than age- and gender-matched cancer-free comparison persons when differences in lifestyle, anthropometry, socioeconomic position or comorbidity where taken into account. To identify potential risk factors, we further investigated the associations between depression and antidepressant use and pre-cancer lifestyle factors, clinical factors and treatment factors. The study results may help point toward vulnerable groups of patients at risk of depression.We investigated the risk of depression in colorectal cancer (CRC) patients and associated risk factors. The 1324 patients with CRC and 6620 matched cancer-free participants from the Diet, Cancer and Health study were followed for up to 16 years for either a first hospitalization for depression or antidepressant prescription after diagnosis of CRC cancer or study entry date. Information on the outcome and covariates was retrieved from the Danish Colorectal Cancer Group database, the national health registries and questionnaires. Cumulative incidence of depression was estimated, and Cox regression models were used to evaluate the association between risk factors and depression incidence. During follow-up, 191 (14.4%) patients with CRC and 175 (2.6%) cancer-free comparison persons experienced depression. After adjustments, in the first year after cancer diagnosis, patients with CRC had a 12-fold higher hazard compared with the cancer-free population (HR, 12.01; 95% CI, 7.89–18.28). The risk decreased during follow-up but remained significantly elevated with an HR of 2.65 (95% CI, 1.61–4.36) after five years. Identified risk factors were presence of comorbidities, advanced disease stage and use of radiotherapy, while life style factors (pre-cancer or at diagnosis) and chemotherapy did not seem to contribute to the increased risk.