The role of hemoglobin levels as an independent prognostic marker of progression to AIDS and/or death in HIV-infected patients starting combination antiretroviral therapy (cART) was investigated. A total of 2579 patients from the EuroSIDA cohort with hemoglobin, CD4 cell count, and HIV RNA viral load measured 6 months prior to starting cART was included in the analyses. Anemia was defined as mild (≤14 g/dl males, ≤12 g/dl females) and severe (<8 g/dl both genders). Poisson regression was used to determine factors related to clinical progression (new AIDS/death). Hemoglobin levels increased by a median of +0.48 g/dl (IQR -0.4 to +1.3) in the first year of cART. During 14,272 person years of follow-up (PYFU) there were 505 new AIDS/deaths. Of the patients 304 (11.8%) developed mild and 19 severe anemia (0.7%). In multivariate analysis baseline hemoglobin was significantly associated with progression to AIDS/death after starting cART with an IRR of 1.07 per 1 g/dl lower (95% CI 1.01-1.13; p = 0.023). When hemoglobin was fitted as a time-updated variable the IRR increased to 1.36 per 1 g/dl lower (95% CI 1.30-1.42; p < 0.001). Starting cART was associated with an increase in hemoglobin levels. Lower hemoglobin values, particularly the latest measured, were associated with an increased risk of disease progression.