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Background: Transthyretin cardiac amyloidosis (ATTR-CM) is an infiltrative cardiomyopathy that frequently progresses to symptomatic heart failure (HF), often with mildly reduced or reduced ejection fraction (EF). Standard therapies are limited in NYHA III–IV, and Tafamidis is approved only for the early stages. Cardiac contractility modulation (CCM) therapy has shown promise in HF with reduced EF, but its role in ATTR-CM remains unexplored. Methods: This multicentric, prospective pilot study evaluated the safety and efficacy of CCM therapy in ten patients (n = 10) with ATTR-CM, EF between 25 and 45%, and NYHA class III–IV symptoms refractory to optimal medical therapy. All patients underwent implantation of the Optimizer CCM system and were followed for at least 12 months. The primary endpoint was the incidence of worsening heart failure (WHF); secondary endpoints included changes in EF, NYHA class, 6-minute walk test (6MWT), and quality of life metrics. Results: In this cohort (n = 10), CCM therapy significantly reduced WHF episodes (from 0.18 ± 0.09 to 0.025 ± 0.08 hospitalizations/patient-year, p < 0.001) and improved NYHA class and 6MWT (p < 0.001). EF increased by an average of 4.8 ± 6.1%, and 6MWT improved by 31.3 ± 53.3%. Importantly, all patients became eligible for Tafamidis after CCM therapy due to improved functional status. Conclusion: This pilot study suggests that CCM therapy is a feasible and potentially effective option for ATTR-CM patients with advanced HF who are not candidates for existing disease-modifying treatments. These findings support the rationale for larger studies, including the ongoing AMY-CCM registry (NCT05167799), to validate CCM’s therapeutic role in this population.