Currently approved medications for the treatment of alcohol dependence are not overwhelmingly effective. Therefore, researchers continue to look for better medications to treat this serious illness. One approach to improve medication efficacy is to target specific medications for treatment resistant subpopulations such as Type B alcoholism, as described by Babor. Type B alcoholics are characterized by an early onset of alcohol problems, greater severity of dependence, and a poor treatment response. In contrast, Type A alcoholics are characterized by a later onset of problem drinking, less severe alcohol dependence, fewer alcohol-related problems, and a better response to treatment. We conducted a double-blind, placebo-controlled, pilot trial, involving 61 alcoholics (32 type A and 29 Type B) treated with quetiapine, 400 mg daily, or placebo. Significantly more quetiapine-treated patients remained abstinent during the trial, compared to placebotreated patients (31% vs. 6%). Quetiapine was significantly more effective in reducing drinking in Type B patients. In Type A patients, both the quetiapine and placebo treated patients significantly reduced their drinking so no effect of quetiapine was detected. Upon further analysis, we found that the characteristic most highly predictive of a good response to quetiapine was frequent heavy drinking as measured by a high average number of drinks per drinking day and a greater number of days of drinking to intoxication in the 30 days prior to the trial. It is likely that the Type A patients in our pilot trial represented a less severely addicted subgroup of alcoholics and this explains why they responded equally well to placebo or quetiapine. Quetiapine may be more effective in frequent heavy drinkers because of associated abnormalities of serotonergic and dopaminergic neurotransmission. Atypical antipsychotics target both the dopamine and the serotonin systems and have shown efficacy in reducing alcohol use in alcoholics with comorbid psychiatric illness. Quetiapine is an atypical antipsychotic that has a favorable side effect profile. The proposed 5-year project is intended to confirm and extend our initial findings regarding quetiapine for the treatment of frequent heavy drinkers in a double-blind, placebo-controlled, 13-week trial. The study will compare quetiapine (400 mg daily) to placebo in 180 DSM-IV alcohol dependent patients who are frequent heavy drinkers as determined by averaging more than 12 drinks per drinking day and having 15 or more days of drinking to intoxication in the thirty days prior to entering the trial. The primary hypotheses are that quetiapine-treated patients will have 1) more abstinent days from alcohol and 2) fewer heavy drinking days compared to placebo-treated patients as measured by the timeline follow back. Exploratory analyses will be conducted to further investigate other possible quetiapine / alcohol subtype interactions