Rationale: Assessment of the inflammatory response can help the decision-making process when diagnosing community-acquired pneumonia (CAP), but there is a lack of information about the influence of time since onset of symptoms. Objectives: We studied the impact of the number of days since onset of symptoms on inflammatory cytokines and biomarker concentrations at CAP diagnosis in hospitalized patients. Methods: We performed a secondary analysis in two prospective cohorts including 541 patients in the derivation cohort and 422 in the validation cohort. The time since onset of symptoms was self-reported, and patients were classified as early presenters (<3 d) and nonearly presenters. Biomarkers (C-reactive protein [CRP] and procalcitonin [PCT] in both cohorts) and cytokines in the derivation cohort (IL-1, - 6, -8, -10, and tumor necrosis factor-α) were measured within 24 hours of hospital admission. Measurements and Main Results: In early presenters, CRP was significantly lower, whereas PCT, IL-6, and IL-8 were higher. Nonearly presenters showed significantly lower PCT, IL-6, and IL-8 levels. In the validation cohort, CRP and PCT exhibited identical patterns: CRP levels were 36.4% greater in patients with 3 or more days since onset of symptoms than in those with less than 3 days since symptom onset in the derivation cohort and 38.2% in the validation cohort. PCT levels were 40% lower in patients with 3 or more days since onset of symptoms in the derivation cohort and 56% in the validation cohort. Conclusions: Time since symptom onset modifies the systemic inflammatory profile at CAP diagnosis. This information has relevant clinical implications for management, and it should be taken into account in the design of future clinical trials.