Lateralized interference between concurrent cognitive and manual activities is used to infer cerebral hemisphere specialization for the cognitive activity. However, some evidence indicates that lateralized interference depends largely on manual asymmetry in the single-task (baseline) condition. To test the competing explanations, we asked 40 right-handed (RH) and 40 left-handed (LH) adults to key press and calculate concurrently. Baseline manual asymmetries were manipulated by increasing the complexity of the task performed by the dominant hand. Nevertheless, in the dual-task conditions, RHs showed more overall interference when performing with the right hand and LHs showed a nonsignificant tendency in the opposite direction. The results indicate that differential interference patterns, similar to those previously reported for right- and left-handers, may be obtained even when the usual baseline manual asymmetries are reversed.