Fresh cut vegetables represent a widely consumed food worldwide. Among these, lettuce (Lactuca sativa L.) is one of the most popular on the market. The growing interest for this "healthy" food is related to the content of bioactive compounds, especially polyphenols, that show many beneficial effects. In this study, we report the anti-inflammatory and antioxidant potential of polyphenols extracted from lettuce (var. Maravilla de Verano), in J774A.1 macrophages stimulated with Escherichia coli lipopolysaccharide (LPS). Lettuce extract significantly decreased reactive oxygen species, nitric oxide release, inducible nitric oxide synthase and cycloxygenase-2 expression. A detailed quali/quantitative profiling of the polyphenolic content was carried out, obtaining fast separation (10 min), good retention time and peak area repeatability, (RSD% 0.80 and 8.68, respectively) as well as linearity (R(2)⩾ 0.999) and mass accuracy (⩽ 5 ppm). Our results show the importance in the diet of this cheap and popular food for his healthy properties.