Familial non-medullary thyroid carcinoma (FNMTC) accounts for approximately 9% of differentiated thyroid cancer (DTC). There is conflicting data on the FNMTC aggressiveness compared with sporadic DTC (sDTC), leading to usually more extensive therapy applied for FNMTC, given its autosomal dominant genetic background. This study aimed to compare the progression-free survival (PFS) in patients with FNMTC and sDTC treated with standard therapy. This longitudinal retrospective cohort study included patients with FNMTC, defined as at least two first-degree relatives affected by DTC. FNMTC patients were matched with sDTC in a 1:3 ratio based on age, sex, American Thyroid Association recurrence risk stratification (ATA-R), extent of initial surgery, and diagnosis date. The primary outcome was PFS. Kaplan-Meier curves were used to compare PFS between the groups, and the Cox proportional hazards model was used to assess confounders. From 95 affected FNMTC patients, 30 were excluded due to lack of follow-up data. The study population consisted of 65 FNMTC and 170 sDTC patients, with a median follow-up of 4.73 (2.87-10.27) years for FNMTC and 5.83 (2.33-10.79) years for sDTC ( = 0.76). There was 100% matching for ATA-R, sex, surgery type, and year of surgery and a satisfactory matching for age (43.12 ± 15.11 vs. 42.76 ± 12.46 years, = 0.85). FNMTC exhibited a smaller tumor size (1.20 ± 0.96 vs. 1.89 ± 1.51 cm, < 0.01) and fewer positive lymph nodes (range 0-13 vs. 0-38, = 0.009) at presentation. The rate of repeated neck surgeries for persistent/recurrent disease was comparable between the groups: 13.8% (9/65) for FNMTC vs. 17.7% (30/170) for sDTC ( = 0.48). There was no difference in radioactive iodine (RAI) therapy dosage between the groups (104 [100-149] vs. 106 [76-160] mCi 0.82). During follow-up, 15.4% of FNMTC and 18.2% of sDTC patients experienced disease progression ( = 0.61). PFS was non-different between groups ( = 0.56) and was associated with ATA-R (high vs. low hazard ratio [HR]: 9.2, confidence interval [CI]: 2.67-31.85, < 0.001) and sex (male vs. female, HR: 2.5, CI: 1.11-5.6, = 0.026). No difference in PFS between FNMTC and sDTC patients suggests comparable responsiveness to standard therapy. Therefore, the management of FNMTC should align with the standard of care for DTC to avoid overtreatment of FNMTC.