What is a normal Interleukin-6 (IL-6) level?

Normal IL-6 Levels in Healthy Adults

In healthy adults, normal serum IL-6 levels are generally less than 5 pg/mL, with a pooled estimate of approximately 5.2 pg/mL (95% CI: 4.6-5.7 pg/mL), though values up to 15 pg/mL may be considered within normal range depending on the assay and clinical context. 1, 2

Reference Ranges Based on Current Evidence

The most comprehensive meta-analysis of IL-6 levels in healthy individuals provides the following parameters:

• Pooled mean estimate: 5.186 pg/mL (95% CI: 4.631-5.740 pg/mL) based on 3,166 healthy donors across 57 studies 1
• Observed range in healthy donors: 0-43.5 pg/mL, though most values cluster at the lower end 1
• Traditional reference range: 5-15 pg/mL has been cited in clinical practice 2
• Upper limit for clinical decision-making: Values below 40 pg/mL are generally associated with favorable outcomes in acute conditions 3

Age-Related Considerations

IL-6 levels increase physiologically with age, with an increment of approximately 0.05 pg/mL per year of life (95% CI: 0.02-0.09 pg/mL; p < 0.01) 1. This means that older adults may have slightly higher baseline IL-6 levels while still being considered healthy.

Assay-Dependent Variability

The stability and reproducibility of IL-6 measurements vary by assay type and sample matrix 4:

• ELISA (single analyte) shows moderate stability over time with correlation coefficients ranging from r = 0.318 to r = 0.660 depending on the time interval 4
• ELISA (Multiplex) demonstrates similar or slightly better stability (r = 0.562 to r = 0.707) 4
• Both plasma and serum are acceptable sample matrices, with comparable stability profiles 4

Clinical Context for Interpretation

Normal IL-6 levels must be interpreted in clinical context, as even "normal" ranges have significant heterogeneity:

• In sepsis and critical illness, IL-6 levels can increase up to 7,500 times normal values, with levels exceeding 7,500 U/mL associated with 89% mortality 3
• In COVID-19, IL-6 levels are elevated but typically 10-40 fold less than in pre-pandemic ARDS 4
• In hematologic malignancies, detectable levels averaging 57 ± 68 pg/mL are common, with 90% of patients exceeding normal donor levels 5
• In chronic inflammatory conditions, IL-6 may range from 15-42 pg/mL during active disease 2

Important Caveats

Several factors limit the universal application of a single reference range:

• Wide variation in cut-off values (12-2,760 pg/mL) across different studies indicates lack of standardization 6, 7
• IL-6 has high biological variability even in healthy individuals, with heterogeneity (I² > 90%) in stability studies 4
• Fasting status, time of day, and acute stressors can transiently elevate IL-6 even in healthy individuals 4
• Different assay platforms and manufacturers may yield different absolute values, though relative changes remain clinically meaningful 4

Practical Recommendation

For clinical decision-making, use the 95% confidence interval of 4.6-5.7 pg/mL as the reference range for healthy adults, with values consistently above 15 pg/mL warranting clinical investigation for underlying inflammatory, infectious, or neoplastic processes 1, 2. Values between 5-15 pg/mL should be interpreted in the context of age, clinical presentation, and serial measurements rather than as isolated findings.