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Background People with human immunodeficiency virus (PWH) have an increased risk of chronic lung diseases and chronic inflammation. We aimed to investigate if inflammatory markers and monocyte activation are associated with faster lung function decline in PWH. Methods We included 655 PWH from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study. Eligible participants were aged ≥25 years and had 2 spirometries separated by >2 years. Inflammatory markers (interleukin [IL]–1β, IL-2, IL-6, IL-10, tumor necrosis factor–α, and interferon-γ) were measured at baseline by Luminex, and soluble CD14 and soluble CD163 by enzyme-linked immunosorbent assay. Using linear mixed models, we investigated whether elevated cytokine levels were associated with faster lung function decline. Results The majority of PWH were males (85.2%) with undetectable viral replication (95.3%). We found a faster decline in forced expiratory volume in 1 second (FEV1) in PWH with elevated IL-1β and IL-10, with an additional decline of 10.3 mL/year (95% confidence interval [CI], 2.1–18.6; P =.014) and 10.0 mL/year (95% CI, 1.8–18.2; P =.017), respectively. We found no interaction between smoking and IL-1β or IL-10 on FEV1 decline. Conclusions Elevated IL-1β and IL-10 were independently associated with faster lung function decline in PWH, suggesting that dysregulated systemic inflammation may play a role in the pathogenesis of chronic lung diseases. [ABSTRACT FROM AUTHOR]