Research findings over the past several decades have shown that inflammation is a prominent feature of many chronic diseases, with poor diet being one likely inflammatory stimulus. Specifically, a single high-fat meal (HFM) has been suggested to increase inflammation, although there is currently no consensus with regard to the specific changes in many of the proinflammatory markers that are frequently assessed after an HFM. The aim of this systematic review was to objectively describe the postprandial timing and magnitude of changes in 5 common inflammatory markers: interleukin (IL) 6, C-reactive protein (CRP), tumor necrosis factor (TNF) a, IL-1b, and IL-8. Ten relevant databases were searched, yielding 494 results, of which 47 articles met the pre-established inclusion criteria: 1) healthy men and women aged 18-60 y, 2) consuming a single HFM ($30% fat, $500 kcal), and 3) assessing relevant inflammatory markers postmeal for $2 h. The only marker found to consistently change in the postprandial period was IL-6: on average, from a baseline of ;1.4 pg/mL, it peaked at ;2.9 pg/mL ;6 h post-HFM (an average relative change of ;100%). CRP, TNF-a, IL-1b, and IL-8 did not change significantly in 79% (23 of 29), 68% (19 of 28), 67% (2 of 3), and 75% (3 of 4) of included studies, respectively. We conclude that there is strong evidence that CRP and TNF-a are not responsive at the usual time scale observed in postprandial studies in healthy humans younger than age 60 y. However, future research should further investigate the role of IL-6 in the postprandial period, because it routinely increases even in healthy participants. We assert that the findings of this systematic review on markers of inflammation in the postprandial period will considerably aid in informing future research and advancing clinical knowledge. Adv Nutr 2017;8:213-25.