The objective of this study was to evaluate the impact on SARS-CoV-2 transmission prevention of mask wearing by index cases and their household contacts. A prospective study of SARS-CoV-2 transmission to household contacts aged ≥18 years was conducted between May 2022 and February 2024 in Spain. Contacts underwent a rapid antigen test on day zero and a real-time polymerase chain reaction test 7 days later if results were negative. The dependent variable was SARS-CoV-2 infection in contacts. Index case and contact mask use effects were estimated using the adjusted odds ratio (aOR) and its 95% confidence interval (CI). Studied were 230 household contacts, mean (standard deviation) age 53.3 (16.6) years, and 47.8% (110/230) women. Following index case diagnosis, 36.1% of contacts (83/230) used a mask, and 54.3% (125/230) were exposed to a mask-wearing index case. Infection incidence in contacts was 45.2% (104/230) and was lower in contacts exposed to mask-wearing index cases (36.0% vs. 56.2%; p < 0.002). The logistic regression model indicated a protective effect for contacts of both index case mask use (aOR = 0.31; 95% CI: 0.15–0.65) and vaccination (aOR = 0.24; 95% CI: 0.08–0.77). Index case mask use reduced SARS-CoV-2 transmission to contacts, while mask effectiveness was not observed for contacts.