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Background. There are few recent data on the rates of AIDS-defining opportunistic infections (OIs) among human immunodeficiency virus (HIV)–infected patients in care in the United States and Canada.Methods. We studied HIV-infected participants in 16 cohorts in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) during 2000–2010. After excluding 16 737 (21%) with any AIDS-defining clinical events documented before NA-ACCORD enrollment, we analyzed incident OIs among the remaining 63 541 persons, most of whom received antiretroviral therapy during the observation. We calculated incidence rates per 100 person-years of observation (hereafter, “person-years”) with 95% confidence intervals (CIs) for the first occurrence of any OI and select individual OIs during 2000–2003, 2004–2007, and 2008–2010.Results. A total of 63 541 persons contributed 261 573 person-years, of whom 5836 (9%) developed at least 1 OI. The incidence rate of any first OI decreased over the 3 observation periods, with 3.0 cases, 2.4 cases, and 1.5 cases per 100 person-years of observation during 2000–2003, 2004–2007, and 2008–2010, respectively (Ptrend<.001); the rates of most individual OIs decreased as well. During 2008–2010, the leading OIs included Pneumocystis jiroveci pneumonia, esophageal candidiasis, and disseminated Mycobacterium avium complex or Mycobacterium kansasii infection.Conclusions. For HIV-infected persons in care during 2000–2010, rates of first OI were relatively low and generally declined over this time.