| Summary: | Obstructive sleep apnea (OSA) and systemic inflammation typically coexist within a vicious cycle. This study aimed at exploring the effectiveness of a weight-loss lifestyle intervention in reducing plasma tumor necrosis factor-alpha (TNF-a), a well-established modulator of systematic inflammation in OSA. Eighty-four adult, overweight patients with a diagnosis of moderate-to-severe OSA were randomized to a standard care (SCG, <i>n</i> = 42) or a Mediterranean lifestyle group (MLG, <i>n</i> = 42). Both groups were prescribed continuous positive airway pressure (CPAP), while the MLG additionally participated in a 6-month behavioral intervention aiming at healthier weight and lifestyle habits according to the Mediterranean pattern. Plasma TNF-a was measured by an immunoenzymatic method both pre- and post-intervention. Drop-out rates were 33% (<i>n</i> = 14) for the SCG and 24% (<i>n</i> = 10) for the MLG. Intention-to-treat analysis (<i>n</i> = 84) revealed a significant decrease in median TNF-a only in the MLG (from 2.92 to 2.00 pg/mL, <i>p</i> = 0.001). Compared to the SCG, the MLG exhibited lower follow-up TNF-a levels (mean difference adjusted for age, sex, baseline TNF-a and CPAP use: −0.97 pg/mL, <i>p</i> = 0.014), and further controlling for weight loss did not attenuate this difference (<i>p</i> = 0.020). Per protocol analyses (<i>n</i> = 60) revealed similar results. In conclusion, a healthy lifestyle intervention can lower plasma TNF-a levels in patients with OSA.
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