The idea that handedness indicates something about a person’s cognitive ability and personality is a perennial issue. A variety of models have been put forward to explain this relationship and predict a range of outcomes from higher levels of cognitive ability in left-handers or moderate right-handers to lower levels of achievement in left- or mixed-handers. We tested these models using a sample (n = 895) drawn from the BRAINnet database (www.brainnet.net). Participants completed a general cognitive ability (GCA) scale and a test of hand preference/performance. Moderate right-handers, as indexed by their performance measures, had higher GCA scores compared with strong left- or right-handers. The performance measure also showed lower levels of GCA for left-handers compared with right-handers. The hand preference data showed little or no association with cognitive ability—perhaps because this measure clusters individuals toward the extremes of the handedness distribution. While adding support to Annett’s heterozygous advantage model, which predicts a cognitive disadvantage for strong left- or right-handers, the data also confirm recent research showing a GCA disadvantage for left-handers. Although this study demonstrates that handedness is related to cognitive ability, the effects are subtle and might only be identified in large-scale studies with sensitive measures of hand performance. (JINS, 2010, 16, 585–592.)