In this contribution we present to our knowledge the first investigations of macromolecular, often called humic-like substances (HULIS) in cloud water samples and compare them with water-soluble extracts from atmospheric PM2.5, soils and waters to study its possible origin. Chemical analysis was done using high performance liquid chromatography (HPLC) coupled with UV and diode array detector, and HPLC coupled with ESI-MS (electrospray ionization mass spectrometer). The data have been treated by principle component analysis (PCA) and cluster analysis to state similarities and/or differences between different types of samples. Our results show that the content of organic and inorganic species is distinctly different in smaller and larger droplets suggesting varying origin. We conclude that smaller droplets are formed more from organic containing condensation nuclei (CCN) and larger droplets more from inorganic containing CCN organic compounds. Putting all experimental findings together we state that HULIS in cloud water—and consequently in particulate CCN precursors—are produced in an atmospheric polymerization process from low molecular weighted organics of different origin. Evidence is found that anthropogenic sources contribute to this pathway. Cloud drops may act as reactor in this HULIS formation process but more likely are gas-phase or gas-to-particle interactions.