Of patients attending HIV clinics, neither the proportion with CD4(+) cell counts below 200 cells/microl, and therefore at risk for developing opportunistic infections (OIs), nor the reasons for the persistence of low CD4(+) cell counts are well known in the era of highly active antiretroviral therapy (HAART). In an effort to gather data concerning this issue, the charts of all outpatients who attended two reference HIV clinics in Spain throughout the year 2001 were retrospectively reviewed. Of 1897 subjects, 213 (11%) had at least one CD4(+) cell count determination below 200 cells/microl during 2001. The main reasons for presenting with low CD4(+) cell counts were as follows: (1) poor treatment adherence, 64 (30%); (2) poor immune recovery despite complete virus suppression for longer than 1 year on HAART, 47 (22%); (3) virologic failure under HAART, 33 (15%); (4) no antiretroviral therapy, 23 (11%); (5) initiation of HAART within the current year in subjects with very low CD4(+) cell counts, 17 (8%); (6) impediment in using HAART due to toxicity, 17 (8%); and (7) drug-induced myelotoxicity, 12 (6%). During the period under review, one or more OIs developed in 52 of the 213 (24%) patients with low CD4(+) cell counts. They occurred more frequently in subjects who were naive for antiretroviral drugs or who initiated therapy recently (RR, 6.45; 95% CI, 2.43-17.12; p < 0.001), and conversely tended to be less frequent among subjects with poor immune reconstitution despite complete virologic suppression while on HAART (RR 0.86; 95% CI, 0.28-2.62; p = 0.79). A lower lifetime CD4(+) cell count nadir was associated with a greater risk of developing an OI (RR, 0.98; 95% CI, 0.97-0.99; p < 0.001). We conclude that, despite the availability of HAART, more than 10% of patients currently attending HIV clinics have CD4(+) cell counts <200 cells/microl, and continue to be at risk for developing OIs. Poor treatment adherence and lack of immune recovery despite complete virus suppression while on HAART account for more than half of cases.