OBJECTIVE To examine the relation between symptoms, initial viral load, and viral load set point in primary HIV infection (PHI). METHODS Prospective cohort of patients with preseroconversion or recent seroconversion HIV infection (typically <60 days) in San Francisco. METHODS Subjects were questioned about 21 potential PHI symptoms at enrollment and were subsequently followed with viral load measures. RESULTS The analysis included 57 subjects with preseroconversion HIV infection and 120 with recent seroconversion. In univariate analysis, most symptoms and the total number of symptoms were each associated with a significantly higher initial viral load. In stepwise multiple linear regression, however, only the number of symptoms was independently associated with a higher initial viral load, with an increase in the initial viral load of 0.08 log10 per additional symptom (P < 0.001). In univariate analysis, more PHI symptoms were associated with a higher viral load set point, but in a multivariable mixed-effects model, this association was accounted for by the initial viral load, which was strongly correlated with viral load set point (R = 0.44, P < 0.001). CONCLUSIONS A high initial viral load was associated with more symptoms during PHI. The strong correlation between initial HIV-1 RNA viral load levels and viral load set point suggests that early interactions between the HIV-1 virus and a new host, even before fully developed adaptive immune responses, are important in establishing viral load set point.