I'm a bit baffled why the results of these two MWE should result in different output at all.
Example 1 (desired output)
In this example, I set the y-coordinate value using a length:
\documentclass{article}
\usepackage{tikz}
\usetikzlibrary{calc}
\setlength{\parindent}{0pt}
\newlength{\mydepth}%
\begin{document}
A
\begin{tikzpicture}
\coordinate (top right) at (0,0);
\setlength\mydepth{\dimexpr2in+2cm\relax}
\coordinate (bottom left) at (4in,-\mydepth);
\draw (bottom left) -- (top right);
\node[draw] (A) at ($(top right)!0.5!(bottom left)$) {CONTENT};
\draw[blue,line width=2pt] (current bounding box.south east) rectangle (current bounding box.north west);
\end{tikzpicture}
\end{document}

Example 2 (icky output)
In this example, I set the y-coordinate value using a macro:
\documentclass{article}
\usepackage{tikz}
\usetikzlibrary{calc}
\setlength{\parindent}{0pt}
\begin{document}
A
\begin{tikzpicture}
\coordinate (top right) at (0,0);
\edef\mydepth{\dimexpr2in+2cm\relax}
\coordinate (bottom left) at (4in,-\mydepth);
\draw (bottom left) -- (top right);
\node[draw] (A) at ($(top right)!0.5!(bottom left)$) {CONTENT};
\draw[blue,line width=2pt] (current bounding box.south east) rectangle (current bounding box.north west);
\end{tikzpicture}
\end{document}

Actually this 2nd example, I don't need the macro. Originally this issue arose with the following code:
\coordinate (bottom left) at (4in,\dimexpr2in+2cm\relax);
So the question isn't really one of macro vs length. It's a matter of calculating lengths in a coordinate.
! You can't use '\dimexpr' in restricted horizontal mode.and no tikz picture – David Carlisle Oct 02 '13 at 00:01\edef\mydepth...outside thetikzpicture. Inside I get no such error. Do you get such an error with\coordinate (bottom left) at (4in,\dimexpr2in+2cm\relax);? – A.Ellett Oct 02 '13 at 00:03\listfilesoutput to my answer – David Carlisle Oct 02 '13 at 00:08\listfilesmight be good. I'm working on my laptop which has the cvs version from 8/23/2013. At home, I have a more recent cvs version (from late September) on my computer. I'll check things out at home too. – A.Ellett Oct 02 '13 at 00:10