In breath analysis, ambient air contaminations are ubiquitous and difficult to eliminate. This study was designed to investigate the reduction of ambient air background by a lung wash-out with synthetic air. The reduction of the initial ambient air volatile organic compound (VOC) intensity was investigated in the breath of 20 volunteers inhaling synthetic air via a sealed full face mask in comparison to inhaling ambient air. Over a period of 30 minutes, breath analysis was conducted using ion mobility spectrometry coupled to a multi-capillary column. A total of 68 VOCs were identified for inhaling ambient air or inhaling synthetic air. By treatment with synthetic air, 39 VOCs decreased in intensity, whereas 29 increased in comparison to inhaling ambient air. In total, seven VOCs were significantly reduced (P-value < 0.05). A complete wash-out of VOCs in this setting was not observed, whereby a statistically significant reduction up to 65% as for terpinolene was achieved. Our setting successfully demonstrated a reduction of ambient air contaminations from the airways by a lung wash-out with synthetic air.