Reversed phase chromatog. (RPC) is often the first choice for peptide purifications when screening conditions at lab or anal. scales and usually generates high purities at high yields. It has some drawbacks however. Its delicate silica backbone has low tolerance to harsh cleaning conditions and can easily become fouled, causing difficulties in resolving some impurities and contaminants, such as polar analytes. To circumvent this problem an orthogonal hydrophilic resin, an agarose-based ion exchange resin (IEX), that tolerates harsh chems. can be introduced upstream of the RPC column. In this study we use a traditional RPC binding buffer, 0.1% TFA, pH 2, as the IEX binding buffer to bind peptides on a cation exchange resin since the peptide will be cationic - the amino acids are protonated - at such a low pH. Employing an acidic pH is advantageous since unknown sequences will be bound to the ligand on the CIEX resin (sulfonate ligand). We will present two case studies where we have tested the feasibility of this proposed generic IEX - RPC purification The two peptides studied had very different properties, on is a complex cyclic basic glucopeptide conjugate and the other one is a linear acidic peptide with low complexity (Bivalirudin). We loaded the peptide crudes (feed purities higher than 80%) onto a CIEX column and further onto an RPC column. We evaluated the purity and yield from this setup and compared it to using both columns as stand-alone columns. The glucopeptide conjugate feed had one very difficult to resolve impurity close to the main peak that was easily resolved on a CIEX resin. The early eluting impurities, the less hydrophobic impurities, which were not properly resolved on RPC were significantly reduced when CIEX was implemented upstream in the purifications, thus showing the orthogonality of these two methods. The combination of CIEX and RPC resulted in high purities and only a small yield loss. In conclusion, initial IEX runs are easily set up using RPC-compatible buffers for screening purposes.