Psychiatric disorders and infections are both common comorbidities among patients with cancer. However, little is known about the role of precancer psychiatric disorders on the subsequent risk of sepsis as a complication of infections among patients with cancer. We conducted a cohort study of 362,500 patients with newly diagnosed cancer during 2006-2014 in Sweden. We used flexible parametric models to calculate the HRs of sepsis after cancer diagnosis in relation to precancer psychiatric disorders and the analyses were performed in two models. In model 1, analyses were adjusted for sex, age at cancer diagnosis, calendar period, region of residence, and type of cancer. In model 2, further adjustments were made for marital status, educational level, cancer stage, infection history, and Charlson Comorbidity Index score. During a median follow-up of 2.6 years, we identified 872 cases of sepsis among patients with cancer with precancer psychiatric disorders (incidence rate, IR, 14.8 per 1,000 person-years) and 12,133 cases among patients with cancer without such disorders (IR, 11.6 per 1000 person-years), leading to a statistically significant association between precancer psychiatric disorders and sepsis in both the simplified (HR, 1.31; 95% CI, 1.22-1.40) and full (HR, 1.26; 95% CI, 1.18-1.35) models. The positive association was consistently noted among patients with different demographic factors or cancer characteristics, for most cancer types, and during the entire follow-up after cancer diagnosis. Collectively, preexisting psychiatric disorders were associated with an increased risk of sepsis after cancer diagnosis, suggesting a need of heightened clinical awareness in this patient group. SIGNIFICANCE: These results call for extended prevention and surveillance of sepsis among patients with cancer with psychiatric comorbidities.