Abstract Background Post-COVID-19 Syndrome (PCS) entails a spectrum of symptoms, including fatigue, reduced physical performance, dyspnea, cognitive impairment, and psychological distress. Given the effectiveness of exercise-based rehabilitation for PCS, this study examined the efficacy of rehabilitation for PCS patients, focusing on sex-specific differences. Methods Prospective cohort study during inpatient rehabilitation. Cardiopulmonary exercise testing and spirometry were performed at admission and discharge. Questionnaires were used to assess fatigue, health-related quality of life, wellbeing, and workability for up to 6 months. Results 145 patients (36% female, 47.1 ± 12.7 years; 64% male, 52.0 ± 9.1 years; p = 0.018) were referred to rehabilitation 262.0 ± 128.8 days after infection (female, 285.5 ± 140.6 days; male, 248.8 ± 112.0 days; p = 0.110). Lead symptoms included fatigue/exercise intolerance (81.4%), shortness of breath (74.5%), and cognitive dysfunction (52.4%). Women presented with higher relative baseline exercise capacity (82.0 ± 14.3%) than males (68.8 ± 13.3%, p < 0.001), but showed greater improvement in submaximal workload (p = 0.026). Men exhibited higher values for FEV1, FEV1/VC, PEF, and MEF and lower VC at baseline (p ≤ 0.038), while FEV1/VC improvement more in women (p = 0.027). Higher baseline fatigue and lower wellbeing was detected in women and correlated with impaired pulmonary function (p < 0.05). Disease perception including fatigue, health-related quality of life, wellbeing and workability improved with rehabilitation for up to six-month. Conclusions Rehabilitation improves cardiopulmonary fitness, pulmonary function and disease burden in women and men with long-term PCS. Women with PCS may benefit from intensified respiratory muscle training. Clinical assessment should include cardiopulmonary exercise testing and pulmonary function tests and fatigue assessments for all PCS patients to document limitations and tailor therapeutical strategies.