Background: Reducing the progress of neurodegeneration is a key goal in Huntington´s disease (HD). A previously performed systematic screening for medications with neuroprotective features identified tricyclic antidepressants and neuroleptics as neuroprotective and mitochondrioprotective agents. Here, we analyzed the characteristics of disease manifestation, progression and potential beneficial effects in HD patients treated with afore-mentioned medications compared to un- and otherwise treated motor-manifest patients in a large real-world cohort over two years. Methods: We analyzed cross-sectional data of the largest cohort worldwide of motor-manifest HD patients using the ENROLL-HD database, including demographic, moleculargenetic, clinical-motoric, cognitive and functional data. Longitudinal data of up to two years were obtained to analyze potential effects on disease progression between groups with different medications used. Data were analyzed using repeated ANOVA-analyses while controlling for the co-variates age and CAG-repeat length. Results: We identified n = 7397 motor-manifest HD patients using no or different medication (HD-ctrl) and subgroups treated with clomipramine (n = 56), clozapine (n = 66), chlorpromazine (n = 17), doxepine (n = 34) and desi-, imi- or trimipramine (n = 19). Demographic parameters, disease onset and CAP-score did not differ. Total motor scores (TMS) at baseline were higher in patients treated with clozapine (p < 0.001), chlorpromazine and clomipramine (p < 0.05) compared to HD-ctrl with higher sub scores for bradykinesia (all p < 0.01) and dystonia in clozapine treated patients (p < 0.001). Functional and cognitive capacities were worse in medication groups in comparison to HD-ctrl at baseline (p < 0.001). Repeated measures analysis of variance documented no differences regarding motoric, functional and cognitive disease progressions between groups. Conclusions: We identified group differences, potentially caused by side effects or potential selection bias in terms of bradykinetic motoric symptoms, more dystonia and lower functional and cognitive performance in some treatment groups at baseline, which were not entirely explained because of underlying fundamental characteristics. Disease progression regarding clinical, functional and cognitive outcomes over two years was not affected by any of the treatment groups compared to HD-ctrl. Our data do not support our hypothesis of a potential neuroprotective effect of these drugs on disease progression. Full article