Abstract Background The inflammatory mediator procalcitonin (PCT) has previously been associated with prognosis in myocardial infarction, cancer and sepsis patients. The importance of PCT in the general population is currently unknown. Our aim was to assess the relationship between plasma PCT and the risk of all-cause and cause-specific mortality in apparently healthy individuals with no previous history of cardiovascular disease or cancer. Methods We performed a prospective, population-based study on 3,322 individuals recruited from the Malmö Diet and Cancer cohort, with a median follow-up time of 16.2 years. Plasma PCT, high-sensitivity C-reactive protein (hsCRP), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides and cystatin C were measured at baseline and a thorough risk factor assessment was performed for all subjects. The primary end-points of the study were all-cause mortality, cancer mortality and cardiovascular mortality. Results Men had higher PCT levels compared to women. In Cox proportional hazard models adjusted for age, sex, hypertension, diabetes, plasma lipids, renal function, body mass index and smoking, baseline PCT was associated with all-cause mortality and cancer mortality in men. The hazard ratio (HR) for men with PCT levels within the highest compared with the lowest quartile was 1.52 (95% confidence interval (CI) 1.07 to 2.16; P = 0.024) for all-cause mortality and 2.37 (95% CI 1.36 to 4.14; P = 0.006) for cancer mortality. Additionally, men with increased plasma PCT were found to be at a higher risk to develop colon cancer (HR per 1 SD increase = 1.49 (95% CI 1.13 to 1.95); P = 0.005). In multivariate Cox regression analyses with mutual adjustments for PCT and hsCRP, PCT was independently associated with cancer death (HR per 1 SD increase = 1.28 (95% CI 1.10 to 1.49); P = 0.001) and hsCRP with cardiovascular death (HR per 1 SD increase = 1.42 (95% CI 1.11 to 1.83); P = 0.006) in men. We found no significant correlations between baseline PCT or hsCRP and incident cancer or cardiovascular death in women. Conclusions We disclose for the first time important independent associations between PCT and the risk for all-cause and cancer mortality in apparently healthy men. Our findings warrant further investigation into the mechanisms underlying the relationship between PCT and cancer.