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In vitro and clinical data were analysed to evaluate the susceptibility profile of itraconazole in light of the new cut-off points. The in vitro activity of itraconazole was compared with that of eight comparators against 119 Candida bloodstream isolates from 2015 to 2018. Minimum inhibitory concentrations (MICs) were measured by the colorimetric MICRONAUT-S assay. The content of wells without any color change was sub-cultured to measure killing efficacy. No major differences were found against Candida albicans. Itraconazole, posaconazole and amphotericin B were the most active agents against Candida parapsilosis. Of the 32 isolates of C. parapsilosis that were resistant to fluconazole, 96.9%, 78.1% and 93.8% were susceptible to itraconazole, voriconazole and posaconazole, respectively. The ratio of the minimum fungicidal concentration (MFC) to the MIC of itraconazole was lower than for the other azoles against C. parapsilosis and C. glabrata. Itraconazole achieved greater inhibition over-time of the growth of C. parapsilosis than fluconazole. Seventy-three critically ill patients who were unresponsive to antibiotics received intravenous empirical treatment with itraconazole (n = 28) or comparators (n = 45). Case-control matching was conducted for severity, comorbidities, risk factors for candidemia, administered antibiotics and days of antifungal treatment. Breakthrough candidemia was found in 3.6% of patients treated with itraconazole and in 32.1% of patients treated with comparators (P: 0.020); breakthrough candidemia by C. parapsilosis was found in 3.6% and 28.6% of patients, respectively. Results indicate that itraconazole retains a valuable susceptibility profile against Candida isolates, particularly C. parapsilosis. This superior profile may explain the clinical efficacy in the occurrence of breakthrough candidemia and warrants further clinical investigation.