Abstract: Objective To investigate the association between the systemic inflammatory response index (SIRI) and lung cancer prevalence based on the National Health and Nutrition Examination Survey (NHANES) database. Methods This cross-sectional study integrated data from 10 consecutive survey cycles of the NHANES database between 1999 and 2018. Multivariable logistic regression models were used to evaluate the association between SIRI and lung cancer prevalence, and a trend test was performed to assess whether there was a linear trend in lung cancer prevalence with increasing SIRI levels. Restricted cubic spline (RCS) analysis was further performed to examine the association and potential nonlinear relationship between SIRI and lung cancer prevalence. Subgroup analyses and sensitivity analyses were conducted to assess the robustness of the results. Results A total of 35 372 participants were included. With increasing SIRI levels, the mean age of participants showed a significant increasing trend (P<0.001). The overall prevalence of lung cancer was 0.21%, with the highest prevalence observed in the Q4 group (0.47%), and the difference among groups was statistically significant (P<0.001). After adjustment for confounding factors, each 1-unit increase in SIRI was associated with an odds ratio (OR) for lung cancer prevalence of 1.36 (95% CI:1.18-1.58, P<0.001). Using the lowest SIRI quartile (Q1) as the reference, the Q4 group had a higher lung cancer prevalence, with an OR of 3.95 (95% CI:1.65-9.45, P=0.002). The trend test showed a significant increasing trend in lung cancer prevalence with increasing SIRI quartiles (P_trend=0.003). RCS analysis revealed a significant overall association between SIRI and lung cancer prevalence (P<0.001), with no significant nonlinear relationship detected (P=0.425). Subgroup analyses indicated no significant interactions across different population characteristics (all Pinteraction > 0.05). Sensitivity analyses showed that the association between SIRI as a continuous variable and lung cancer prevalence remained significant (OR=1.34, 95% CI:1.20-1.51, P<0.001). Conclusions Elevated SIRI levels are positively associated with increased lung cancer prevalence, and this association is robust. SIRI, as a simple and cost-effective inflammatory marker, has potential value in risk stratification for lung cancer prevalence.