In Windows, I have my mouse configured for left-handed use (so "left"-button clicking is on the right), but the game is not recognizing this setting, or is overriding it. How can I get the mouse to work left-handed? thx.

What mouse are you using? Most of them allow to map custom functions to their buttons in their control panel. If it offers a general switch of primary and secondary button, don't use this option, but map the mouse buttons explicitly to left-click and right-click, so that the function of the right mouse button is a left-click and vice versa.

Usually custom mouse settings can also be set for specific programs only. Make sure Giana Sisters isn't on that list while set to standard behavior.

Thank you both. My Logitech mouse has no separate control panel so I'm going to go ahead with the autohotkey software.

You've probably only installed the standard drivers for your mouse. Logitech also offers utility software, e.g. for mouse buttons customization. It's pretty likely that the Logitech utility works for your mouse ([url=http://www.logitech.com/en-us/support/3131?section=downloads]download link)