BACKGROUND AND AIM: The relationship between the systemic inflammatory response index (SIRI) and carotid atherosclerosis has not yet been assessed in a longitudinal investigation. Our current study aimed to investigate whether SIRI is related to an increased risk of incident carotid plaque. METHODS AND RESULTS: Our study included individuals who did not have carotid atherosclerosis and had undergone yearly health check-ups at the Department of Health Management of Nanfang Hospital between 2011 and 2018 (total n = 3927). SIRI was computed by a composite value of neutrophils, monocytes, and lymphocytes. Over a median follow-up time of 4.42 years, 872 (22.21 %) participants developed carotid plaque in the entire cohort. The adjusted hazard ratio (HR) for the continuous SIRI was 1.093 (95 % CI: 1.021-1.223) in our present study. In the general population, individuals belonging to the highest quartile of SIRI had an elevated risk of carotid plaque, as compared to those within the lowest quartile (HR 1.122, 95 % CI: 1.011-1.391, P for trend = 0.041). Furthermore, this trend was even more pronounced among participants without hypertension, diabetes and hyperlipidemia in the highest SIRI quartile, who demonstrated a markedly increased risk of carotid plaque when contrasted with those in the lowest quartile (HR 1.277, 95 % CI: 1.041-1.568, P for trend = 0.006). CONCLUSIONS: Our research findings suggest an association between increased SIRI levels and a higher incidence of carotid atherosclerosis, especially among the people without a history of hypertension, diabetes and hyperlipidemia.