To clarify the frequency and prognostic significance of a plasma human immunodeficiency virus (HIV) RNA load below the detection threshold during the natural history of infection, an ultrasensitive assay was used to identify persons with low virus loads in a cohort of 111 untreated subjects with a known date of seroconversion. Six persons had HIV RNA loads <40 viral copies (VC)/mL during the first years of HIV infection. The probability of meeting the criteria for long-term nonprogression was higher in these subjects (P=.043). However, a virus load <40 VC/mL was rare during the natural history of infection, even during the first years of symptomless HIV carriage. Such data confirm the general trend of disease progression in the entire population of HIV carriers.