Margaret Robertson is the former editor of my favorite (by far) gaming magazine, Edge. She now writes a terrific blog called Downtime that she hopes "won't be tedious or lame." Trust me, it is neither. You should definitely check it out.
In her most recent post she reexamines the question of why so few women play games and calls for a closer examination of basic gameplay issues as a likely culprit.
In asking why more women don't play games, we worried a lot, initially, about surface things - boy-games were too violent, too lasers-and-robots. What we needed was girl-games about shopping, horses and make-up! Now, thankfully, we've moved a little past that (despite the fact that games about shopping, horses and make-up do seem to be proving particularly successful with young female consumers, particularly on the DS), and are looking at important external factors. So we've noted that for games to be attractive to women they need to be available on hardware they feel comfortable with, and offer play-patterns that are compatible with busy, often fragmented lives.
My experience observing male gamers in my classes suggests that most of them have developed an easy familiarity with the gamepad, to the extent that they can elucidate in specific detail why the current Xbox 360 controller is superior to the Dualshock controller for the PS2...or vice versa. Their relative discomfort with computer games, on the other hand, has less to do with the quality of the games themselves than with the WASD keyboard and mouse control scheme, which they find awkward and cumbersome...the very thing many many of us computer gamers felt the first time we were handed a gamepad.
Obviously, game content matters. But as Robinson points out, feeling comfortable with the hardware is less a gender difference issue than an ease of use issue. If you missed the original Atari 1-button joystick bus when it left the station, it's hard to jump on the 7-button, 4-trigger, 2-joystick, 4-way directional pad bus currently barreling down the road.