COPD remains common and complex with huge costs on the NHS and disruption to patients' daily lives. This presents a challenge for an effective, non-invasive test to enable determination and monitoring of COPD status. Fourier transform infrared (FTIR) spectroscopy for sputum profiling is timely. FTIR identifies and measures chemical bond vibrations within functional groups in complex biological mixtures by producing infrared absorption spectra. Identifying COPD-relevant spectra in sputum could provide sensitive rapid information on status and exacerbations. To address this, we randomly recruited 102 patients independent of severity. Sputum was collected at initial visit and in each of subsequent 2 weeks. Dyspnoea and sputum scores were obtained; FEV1, serum CRP and exhaled NO measured; any intervening chest infection or treatment change documented. Patients was stratified by FEV1; 26 patients had mild COPD (FEV1≥80%); 41 moderate (FEV1 49–79%); 35 severe (FEV1 ≤50%). FTIR was performed using an Alpha-T spectrometer (Bruker UK); transmission mode in 4000 to 900 cm−1 region; 4 cm−1 resolution. All COPD sputa gave reproducible biological IR spectra with distinct signatures in 5 key regions at 3300–3280 cm−1 (assigned as amide A), 3000–2800 cm−1, 1660–1600 cm−1 (Amide I), 1560–1520 cm−1 (Amide II) and 1180–1000 cm−1 (glycoproteins). Multivariate analysis showed significant correlation between spectral profiles and FEV1 and smoking habit. The accuracy of differentiating mild from severe COPD was consistently greater than 70% (AUC under ROC curve); specifically we observed peak shifts in Amide A towards 3300 cm−1 as COPD worsened (p<0.001). Also 68/102 patients exhibited a clear band around 2060 cm−1; the remaining 34 showed no band in this region. There was a significant association (p=0.012) between peak presence and COPD severity; with mild COPD patients more likely to have a peak, and severe sufferers having 2060 cm−1 signal absence. 35/102 patients had exacerbations during the study. Separate spectral analysis showed significant increase in glycoprotein max peak during COPD exacerbation (p<0.03). This study has important implications for future near-patient COPD monitoring. FTIR sputum profiling enables non-invasive rapid sampling and evaluation, producing spectral signatures that can differentiate COPD status or predict exacerbation presence.