Abstract Functional somatic symptoms (FSS) are symptoms unexplained in terms of underlying organic pathology. Alterations in the immune system function may be associated with FSS via induction of sickness behavior. We aimed to investigate whether low-grade immune system activation is positively associated with FSS in a population-based cohort of 881 adults (46% male, mean age 53.0, SD 11.4). Participants completed the somatization section of the Composite International Diagnostic Interview surveying the presence of 43 FSS. Innate immune function was assessed by measuring high-sensitive C-reactive protein (hs-CRP). Follow-up measurements of hs-CRP and FSS were performed approximately 2 years later. Regression analyses, with adjustments for gender, age, body mass index, anxiety, depression, smoking, alcohol use, and frequency of exercise, did not reveal a cross-sectional association ( β = 0.01, t = 0.40, p = 0.693) or longitudinal association ( β = −0.03, t = −0.93, p = 0.352) between hs-CRP and the total number of FSS. When examining different bodily clusters of FSS, hs-CRP was not associated with the gastrointestinal FSS cluster, but the association approached statistical significance for the general FSS cluster (OR 1.08, 95% CI 0.98–1.18) and musculoskeletal FSS cluster (OR 1.08, 95% CI 0.99–1.17). For the latter association, exploratory analyses revealed that mainly the pure musculoskeletal complaints were responsible (OR 1.12, 95% CI 1.03–1.21). We conclude that the level of hs-CRP is not a biomarker for the total number of FSS in the general population. The association between hs-CRP and musculoskeletal and general FSS needs further study.