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BACKGROUND: Blood donations in the United States have been screened for antibody to human T-cell lymphotropic virus types I and II (HTLV-I/II) since November 1988. Although clinically diagnosed illness associated with HTLV-I/II remains relatively uncommon, blood donors notified of HTLV infection frequently report negative psychological and social effects following notification. STUDY DESIGN AND METHODS: To assess psychological outcomes, the General Well-Being Scale, a standardized 18- item questionnaire, was administered to 464 HTLV-I/II-positive donors and 91 sex partners at five blood centers in the United States following notification of HTLV-I/II infection. The questionnaire was also given to 735 HTLV-I/II-negative donors. RESULTS: Scores for donors seropositive for HTLV-I and HTLV-II showed significantly more psychological distress than did scores for seronegative donors (p < 0.0005) or a large national sample (p < 0.05). Both HTLV-I (p = 0.02) and HTLV-II (p = 0.01) seropositivity remained significant predictors of lower overall well-being scores after analysis controlling for race, age, gender, education, income, donation type, time since notification, self-reported health status, and intravenous drug use. Variables that predicted higher overall scores were negative HTLV status, older age, higher income, better health, fewer sick days, and fewer work limitations due to health problems. CONCLUSION: Increased psychological distress may be related to notification of HTLV infection among blood donors in the United States.