The dipyrromethane + aldehyde condensation is a common method for the synthesis of trans-A₂B₂-porphyrins, but is often plagued by scrambling processes that lead to a mixture of porphyrins. The problem of scrambling is more pronounced with unhindered dipyrromethanes (e.g., 5-phenyldipyrromethane) than with hindered dipyrromethanes (e.g., 5-mesityldipyrromethane). We have characterized the oligomer composition (by LD-MS), yield of porphyrin (by UV–Vis), yield of N-confused porphyrin (by HPLC), and level of unreacted aldehyde (by TLC) in dipyrromethane + aldehyde condensations leading to trans-A₂B₂-porphyrins. Reaction conditions known to suppress scrambling in reactions involving 5-phenyldipyrromethane (PDPM) were compared to conditions known to provide extensive scrambling. The low-scrambling conditions were found to suppress scrambling by inhibiting reaction of oligomer fragments generated by acid-induced cleavage of the dipyrromethane, rather than by inhibiting acidolysis itself. However, such reaction conditions were also found to inhibit the condensation, leading to low yields (<10%) of porphyrin. The condensation of PDPM + aldehyde was also compared to reactions involving 5-mesityldipyrromethane (MDPM) to understand why trans-A₂B₂-porphyrins can be prepared in good yield devoid of scrambling from reactions using MDPM. The absence of scrambling in MDPM + aldehyde condensations was due to the resistance of MDPM to acidolysis. Taken together, these studies provide insight into the origin of scrambling with different types of substrates under different reaction conditions in the dipyrromethane + aldehyde route to trans-A₂B₂-porphyrins.