The authors describe some aspects of "difficult to treat" infections, pointing out, on the basis of their experience, infective endocarditis (IE) and nosocomial infections in compromised host. Among difficult-to-treat IE, the authors stress: 1) the peculiar etio-epidemiological features and the frequent causative pathogens multiresistance on early post-surgical IE; 2) the problems in detecting and management of IE by HACEK group microorganisms; 3) the problems related to other unusual agents IE, with particular regard to nutritionally deficient variants of S. viridans and to Coxiella burnetii. Among nosocomial infections in compromised host, Authors underline the relationship between either nosocomial flora or surgical/instrumental practices and possible underlying immunodeficiencies. Clinical and diagnostic remarks of sepsis, pneumonitis, meningitis, enteritis in neutropenic patients are then stressed, pointing out their atypical presentations and severe prognosis.