Objective. To study the value of the inflammatory markers (interleukin-6 (IL-6), interleukin-8 (IL-8), and C-reactive protein (CRP)) in predicting the outcome of noninvasive ventilation (NIV) in the management of acute respiratory failure (ARF) on top of chronic obstructive pulmonary disease (COPD) and the role of bacteria in the systemic inflammation. Methods. Thirty three patients were subjected to standard treatment plus NIV, and accordingly, they were classified into responders and nonresponders. Serum samples were collected for IL-6, IL-8, and CRP analysis. Sputum samples were taken for microbiological evaluation. Results. A wide spectrum of bacteria was revealed; Gram-negative and atypical bacteria were the most common (31% and 28% resp.; single or copathogen). IL-8 and dyspnea grade was significantly higher in the non-responder group ( 𝑃 = 0 . 0 1 and 0.023 resp.). IL-6 correlated positivity with the presence of infection and type of pathogen ( 𝑃 = 0 . 0 3 8 and 0.034 resp.). Gram-negative bacteria were associated with higher significant IL-6 in comparison between others ( 1 9 6 . 4 ± 2 3 9 . 1 pg/dL; 𝑃 = 0 . 0 1 1 ) but insignificantly affected NIV outcome ( 𝑃 > 0 . 0 5 ). Conclusions. High systemic inflammation could predict failure of NIV. G-ve bacteria correlated with high IL-6 but did not affect the response to NIV.