Rufus of Ephesus was a leading Greek physician during the Roman Empire, flourishing during the reign of Trajan [98-117]. He was well known for the richness of his clinical descriptions. Galen relied heavily on Rufus for his interpretation of melancholia. Rufus' work is lost and known only through citations in other works. It did have wide influence in the Middle ages through Arabic translation.

He saw melancholia as the result of too much thinking or sadness. His influence in this regard was significant in limiting the concept of melancholia to strictly medical entity. Previously, for example, Aristotle had seen the melancholic temeperament as potentially resulting either in intellectual preeminence or melancholia the disease. Following Rufus, what had been "the tragic destiny of the man of genius became merely the 'spleen' of the overworked scholar."
 

The accumulation of black bile was crucial in explaining melancholia for Rufus. Its coldness and dryness and the "thickened superfluities' that it it caused explained many symptoms.