Increased early-onset bipolar illness was seen in the US compared with the Netherlands and Germany (abbreviated here as Europe), but other clinical characteristics, medication use, and treatment response have not been systematically explored. Outpatients with bipolar disorder were treated naturalistically and followed prospectively at four sites in the US and three in Europe. Data and clinical characteristics were collected from patient questionnaires, and medication usage and good-to-excellent response to treatment for at least 6 months ascertained from daily clinician ratings on the National Institutes of Mental Health-Life Chart Method. Almost all clinical characteristics earlier associated with a poor treatment response were more prevalent in the US than in Europe, including early onset, environmental adversity, rapid cycling, more than 20 prior episodes, comorbid anxiety and substance abuse disorders, and a positive parental history for an affective disorder. Lithium was used more frequently in Europe than in the US and had a higher rate of success, whereas valproate was used more in the US, with a trend toward higher success in Europe. Antidepressants were used more in the US, but had extremely low success rates. Many other agents were deployed differently on the two continents, but success rates were consistently lower in the US than in Europe. In conclusion, clinical characteristics and patterns of medication usage and effectiveness differed markedly in the two continents suggesting the need for uncovering explanations and considering the two populations as heterogeneous in the future pharmacological studies.