Genetic anticipation refers to an inheritance pattern within a pedigree showing a decrease in age of onset or an increase in disease severity or both in successive generations. This phenomenon has become the focus of important research in schizophrenia and bipolar mood disorder. The results to date have been controversial and far from conclusive. To attempt to resolve some of the earlier findings, we compared age at onset and disease severity between two generations in 24 Portuguese families ascertained for genetic linkage studies of bipolar mood disorder. There was a significant decrease in age of onset (P<. 00001) and increase in frequency of episodes (P<.0001)from the first to the second generation. This difference was significant under each of the four data-sampling schemes, one of which excluded probands. The second generation experienced onset 12.4 to 15.9 years earlier and illness 2.3 to 2.6 times more severe than did the first generation. We found no evidence for a specific effect in anticipation related to the transmitting parent's sex. Results of the present study, analyzed carefully for a variety of possible biases, suggest evidence for genetic anticipation in these Portuguese bipolar families.