Background To date, no sufficient reports have studied the effects of sofosbuvir-based hepatitis C virus (HCV) treatment regimens on chronic obstructive pulmonary disease (COPD) exacerbation. Aim The aim was to evaluate the effects of sofosbuvir-based regimens on COPD in relation to exacerbation and lung functions. Patients and methods A total of 240 patients with stable COPD were included and classified into three groups. Group A included 60 patients receiving HCV treatment, group B included 60 patients not candidate for treatment, and group C included 120 negative HCV. They were followed up for the period of treatment and subsequently for 1 year to assess the effect of treatment on exacerbation frequency, pulmonary functions, and quality of life assessed by St. George’s Respiratory Questionnaire, and change of exacerbation pattern. Results After 1 year, there was a significant higher exacerbation correlated with untreated group, whereas groups A and C experienced the same exacerbation frequency. Moreover, the annual decline in forced expiratory volume in 1 s was highly significantly lower in group B, whereas unchanged in other groups. Regression analysis revealed that current smoking and untreated HCV group were predictors of exacerbation, whereas treatment itself did not predispose to exacerbation . During the period of treatment, less than 20% in groups A and C experienced only one exacerbation reported between weeks 6 and 12, whereas all patients in group B experienced at least one or two exacerbations: the first one was reported between weeks 2 and 10, and the other one was between weeks 10 and 12. Conclusion Sofosbuvir-based regimens are considered safe to be used in Patients with COPD and are not associated with exacerbation. Moreover, untreated HCV had deleterious effects on pulmonary functions and quality of life.