Sofrito is a Mediterranean tomato-based sauce that typically also contains olive oil, onion, and garlic. The preparation of sofrito modifies the bioactive compounds (carotenoids and polyphenols) in the ingredients to more bioavailable forms, promoting cis-lycopene formation and polyphenol bioaccessibility. To evaluate the health benefits of this cooking technique, the effect of consuming an acute dose of sofrito on the inflammatory status was studied. In a clinical trial, 22 healthy male subjects consumed a single dose of sofrito (240 g/70 kg) after three days without ingesting any tomato products and following a low-antioxidant diet the day before the intervention. Plasma carotenoids and total polyphenol excretion (TPE) were evaluated, as well as the inflammatory biomarkers C-reactive protein (CRP), interleukin-6 (IL-6), interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α). After the sofrito intake, a significant decrease in CRP (p = 0.010) and TNF-α (p = 0.011) was observed, but only TNF-α was inversely correlated with an increase in TPE and plasma β-carotene (not the major carotenoid, lycopene). The positive health effects of this tomato-based product may be attributed not only to lycopene, but to the bioactive compounds of all the ingredients.