Background <p>Serum triglycerides have been believed to play a key role in the pathophysiology of hypertriglyceridemia-associated acute pancreatitis (HTG-AP). However, mechanistic studies have shown that high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) may also be involved. We aimed to investigate whether admission levels of HDL-C and ApoA-I were associated with adverse outcomes in HTG-AP.</p> Methods <p>Participants enrolled in the national PERFORM registry between November 2020 and November 2023, with available HDL-C and ApoA-I levels at enrollment, were retrospectively analyzed. The primary outcome was persistent organ failure (POF) within 14&#xa0;days. Multivariable logistic regression models were used to examine the association of tertiles of HDL-C and ApoA-I with POF risk. Cochran–Armitage trend test and restricted cubic splines were performed to explore the dose–response relationship.</p> Results <p>Among the 325 patients eventually included, 52 (16.0%) developed POF. Within each low-to-high tertile of ApoA-I, the rate of POF decreased proportionally (<i>p</i> &lt; 0.001 by Cochran–Armitage trend test). After controlling for selected confounders, the highest tertile of ApoA-I was significantly associated with reduced risk of POF when compared with the lowest tertile (adjusted OR = 0.16, 95% CI 0.05–0.56, <i>p</i> = 0.004). Furthermore, spline analyses demonstrated a decrease in the risk of POF with increasing ApoA-I levels (<i>p</i> for overall = 0.021). However, no significant association between HDL-C levels and POF was identified, regardless of regression and trend analyses.</p> Conclusions <p>ApoA-I, but not HDL-C, was inversely associated with the risk of developing POF in HTG-AP patients.</p> <p><i>Trial registration</i>: The PERFORM study was registered in the Chinese Clinical Trial Registry (ChiCTR2000039541), on October 30, 2020.</p>