Though depression is known to frequently afflict those with chronic HIV, mood during the early course of HIV is not well characterized. In a prospective study we assessed mood during primary HIV infection [primary HIV infection (PHI), <1 year duration], its association with neuropsychological performance and markers of neurological disease, and its longitudinal course including effects of antiretroviral therapy (ART). The Beck Depression Inventory (BDI) and Profile of Mood States (POMS) subscales were longitudinally administered prior to and after ART in PHI subjects. This evaluation of mood was done concurrently with blood, cerebrospinal fluid (CSF) and neuropsychological [total z and global deficit score (GDS)] evaluation at each visit. Analysis employed Spearman's rho, logistic regression, and linear mixed models. 47.7 % of the 65 men recruited at a median 3.5 months HIV duration met BDI criteria for clinical depression at baseline, classified as 'mild' (n = 11), 'moderate' (n = 11), or 'severe' (n = 9). Drug, alcohol, and depression history did not associate with BDI score. Proportional somatic-performance scores were worse than cognitive-affective scores (p = .0045). Vigor subscore of POMS was reduced compared to norms and correlated with total z (r = 0.33, p = 0.013) and GDS (r = -0.32, p = 0.016). BDI and POMS correlated with one another (r = 0.85, p < .0001), but not with CSF or plasma HIV RNA, WBC, albumin ratio or neopterin. Improvement was not observed in BDI and POMS over 330 total follow-up visits, even after initiation of ART. Depression was prevalent during PHI in our subjects, associated with abnormal somatic-performance and vigor scores. Neither neuropsychological performance nor disease biomarkers correlated with depressed mood. Mood indices did not improve over time in the presence of ART.