Abstract Background Despite the causal relationship between obesity and colon cancer being firmly established, the effect of obesity on the course of cancer calls for further elucidation. The objective of this study was to assess differences in clinical-pathological and psychosocial variables between obese and nonobese individuals with colon cancer. Materials and Methods This was a prospective, multicentric, observational study conducted from 2015–2018. The sample comprised patients with stage II–III, resected colon cancer about to initiate adjuvant chemotherapy with fluoropyrimidine in monotherapy or associated with oxaliplatin and grouped into nonobese (body mass index <30 kg/m2) or obese (≥30 kg/m2). Subjects completed questionnaires appraising quality of life (European Organization for Research and Treatment of Cancer Quality of Life Core questionnaire), coping (Mini-Mental Adjustment to Cancer), psychological distress (Brief Symptom Inventory 18), perceived social support (Multidimensional Scale of Perceived Social Support), personality (Big Five Inventory 10), and pain (Brief Pain Inventory). Toxicity, chemotherapy compliance, 12-month recurrence, and mortality rate data were recorded. Results Seventy-nine of the 402 individuals recruited (19.7%) were obese. Obese subjects exhibited more comorbidities (≥2 comorbidities, 46.8% vs. 30.3%, p = .001) and expressed feeling slightly more postoperative pain (small size-effect). There was more depression, greater helplessness, less perceived social support from friends, and greater extraversion among the obese versus nonobese subjects (all p < .04). The nonobese group treated with fluoropyrimidine and oxaliplatin suffered more grade 3–4 hematological toxicity (p = .035), whereas the obese had higher rates of treatment withdrawal (17.7% vs. 7.7%, p = .033) and more recurrences (10.1% vs. 3.7%, p = .025). No differences in sociodemographic, quality of life, or 12-month survival variables were detected. Conclusion Obesity appears to affect how people confront cancer, as well as their tolerance to oncological treatment and relapse. Implications for Practice Obesity is a causal factor and affects prognosis in colorectal cancer. Obese patients displayed more comorbidities, more pain after cancer surgery, worse coping, and more depression and perceived less social support than nonobese patients. Severe hematological toxicity was more frequent among nonobese patients, whereas rates of withdrawal from adjuvant chemotherapy were higher in the obese cohort, and during follow-up, obese patients presented greater 12-month recurrence rates. With the growing and maintained increase of obesity and the cancers associated with it, including colorectal cancer, the approach to these more fragile cases that have a worse prognosis must be adapted to improve outcomes.