HIV- 1 protease inhibitors ( PIs) may improve hematopoietic functions owing to their direct effects on bone marrow ( BM) progenitor cells. In this study we investigated this hypothesis evaluating the effect of adding ritonavir ( RTV) and indinavir ( IND) on hematopoietic colony formation assays by colony- forming cell ( CFC) and long- term culture- initiating cell ( LTC- IC) assays, on apoptosis, on cytokine production and stromal cells, in subjects with HIV- 1 infection, and in seronegative controls. After PI addition, CFC and LTC- IC assays in HIV- 1- infected patients showed levels of colony growth significantly higher than those observed at baseline; the same PI activity on colony formation was observed in healthy subjects. No significant modifications on Fas, the membrane form of Fas ( mFas) and Fas- ligand ( FasL) expression, and on cytokine production were observed at BM level after the addition of PIs. At baseline, in HIV- 1- infected patients, the majority of the stromal cells appeared as large and rounded, whereas after the addition of RTV or IND the stromal cells exhibited a fibroblast- like morphology and produced higher stem cell factor ( SCF) and lower MIP- 1alpha levels when compared with the stromal production without the addition of IND. RTV and IND increased colony growth of BM obtained either from HIV- 1- infected patients or from normal individuals, in parallel with the normalization of functional and morphological characteristics of stromal cells.