[LudiusMaximus]

Originally Posted by Rilgamon May be the first thing when Setitem fires is that it calls a clear for the tooltip?

OK, turns out you were right. I got another addon hooking OnTooltipSetItem executing ClearLines().
If that goes first, it's like:

GameTooltip:HookScript("OnTooltipSetItem", function(self)
  self:ClearLines()
  self:AddLine("hi")
end)

GameTooltip:HookScript("OnTooltipSetItem", function() print(GetTime(), "SetItem") end)
GameTooltip:HookScript("OnTooltipCleared", function() print(GetTime(), "Cleared") end)

Leading to

3679.479 Cleared
3679.479 SetItem
3679.629 Cleared
3679.629 Cleared
3679.629 SetItem
3679.831 Cleared
3679.831 Cleared
3679.831 SetItem
3680.031 Cleared
3680.031 Cleared
3680.031 SetItem
...

If it comes second, it's like:

GameTooltip:HookScript("OnTooltipSetItem", function() print(GetTime(), "SetItem") end)
GameTooltip:HookScript("OnTooltipCleared", function() print(GetTime(), "Cleared") end)

GameTooltip:HookScript("OnTooltipSetItem", function(self)
  self:ClearLines()
  self:AddLine("hi")
end)

leading to

4264.37 SetItem
4264.37 Cleared
4264.553 Cleared
4264.553 SetItem
4264.553 Cleared
4264.754 Cleared
4264.754 SetItem
4264.754 Cleared
4264.956 Cleared
4264.956 SetItem
4264.956 Cleared
...

Thanks!