BACKGROUNDStem lettuce is a medicinal and edible plant. The peels, accounting for 300–400 g kg−1 raw stem lettuce and containing polysaccharides 200 g kg−1, are discarded as industrial waste, causing environment pollution and resource waste.RESULTSA polysaccharide named PPSL10‐2 was obtained from the peels of stem lettuce after hot water extraction, and gradation with cascade ultrafiltration and purification using DEAE‐Sepharose cellulose. The purity and molecular weight of PPSL10‐2 is 96.10% and 2.2 × 104 Da respectively, as detected by high‐performance gel permeation chromatography. PPSL10‐2 was found to be an α‐(1→4)‐d‐glucan that branched at O‐6 with a terminal 1‐linked α‐d‐Glcp as side chain, and devoid of helix conformation, which was characterized by monosaccharide composition analysis, Fourier‐transform infrared spectroscopy, Congo red test, scanning electron microscopy, methylation analysis and NMR spectroscopy. Furthermore, PPSL10‐2 exhibited potent immune‐enhancing effect by improving proliferation and phagocytosis, promoting the secretion of nitric oxide and cytokines, as well as the expression of related genes in RAW264.7 macrophages.CONCLUSIONThe findings of the present study suggest that peels as an agricultural by‐product of stem lettuce are good sources of polysaccharides, which could be developed as immunopotentiator for improving human health. © 2023 Society of Chemical Industry.