In contrast to the many reports of successful cases of personalized bacteriophage therapy, randomized controlled trials of non-personalized bacteriophage products did not bring the expected results. Here, we present the outcomes of a retrospective, observational analysis of the first 100 consecutive cases of personalized bacteriophage therapy of difficult-to-treat infections facilitated by a Belgian consortium. The most common indications were lower respiratory tract, skin & soft tissue, and bone infections, and involved combinations of 26 bacteriophages, individually selected and sometimes pre-adapted to target the causative bacterial pathogens. Clinical improvement and eradication of the targeted bacteria were reported for 77.2% and 61.3% of infections, respectively. Eradication was 70% less probable when no concomitant antibiotics were used (odds-ratio = 0.3; 95% confidence interval = 0.127–0.749). In vivo selection of bacteriophage resistance and in vitro bacteriophage-antibiotic synergy were documented in 43.8% (7/16 patients) and 90% (9/10) of evaluated patients, respectively. Bacteriophage immune neutralization was observed in 38.5% (5/13) of screened patients. (BT100 study, ClinicalTrials.gov registration: NCT05498363.)