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Background Hydroxyurea (HU) resistance and intolerance occurs in 15-24% of patients with polycythemia vera (PV). Resistance to HU is associated with a shortened life expectancy. Intolerance has no prognostic significance. Until recently in Belgium there were few therapeutic alternatives for this subgroup of patients. Methods We retrospectively analyzed 106 patients with polycythemia vera who were treated with HU at the University Hospitals of Leuven between 1990 and 2016. We assessed HU intolerance/resistance using a modification of the ELN criteria, using the maximum tolerable dose of HU instead of a minimum dose of 2g per day. Results The median age of patients was 63 years with a male/female ratio of 1.25. An acquired mutation of JAK2 was detected in 101 patients (95.24%). Forty-six patients (48.94%) had a white blood cell count above 10.0 x 109/L at time of diagnosis. After a mean length of treatment of 5.1 years, in total 42 patients (39.62%) were resistant or intolerant to HU. Resistance occurred in 25 (23.58%) and intolerance in 17 patients (16.04%). The main reason of resistance was need of phlebotomy to control the hematocrit and occurred in 17 out of 106 patients (15.74%). Leg ulcer was the most frequent adverse reaction and was reported by 11 out of 106 patients (10.38%). Conclusions Nearly 40% of patients with PV were resistant or intolerant to HU. More research is needed to evaluate the prognostic significance of HU resistance/intolerance using the modified ELN criteria. Since May 2017 ruxolitinib is reimbursed for this subgroup of patients. PEGylated interferon and histone deacetylase inhibitors are being evaluated and may in the future be considered as second-line treatment of PV in Belgium.