Background: Coronavirus disease 2019 (COVID-19) has been threatening the world for more than 2 years. Breakthrough COVID-19 infection has clinical and public health significance. The health care workers have been working in front line; thus, acquiring greatest risks. Their family members are also at high risk being close contact to them. This study aimed to assess the prevalence and the severity of breakthrough COVID-19 infection (BTI) in fourth wave among health care workers (HCW) and their family members, and the protective effect of C OVID-19 vaccine in Myanmar. Methods: A cross-sectional descriptive study was conducted among health care workers (HCW) and their family members who developed confirmed COVID-19 infection either by rapid test or PCR test at least 14 days after receiving COVID-19 vaccine during the fourth wave from January 2022 to May 2022. Data were collected by using standardized forms and analysis was done. Results: A total of 1013 participants were included in this study; 227 HCW and 786 family members. Less than half of HCW 44.4% (101/227) and 17.1% (135/786) of family members suffered BTI in fourth wave. Among them, 95% (96/101) of HCW and 57% (76/135) of family members had at least 3 doses of vaccine. The the chances of getting BTI after taking 3 doses, 4 doses and 5 dose were 47.4%, 36.1% and 10% respectively in HCW; and, 32.8%, 22.4% and 1% respectively in the family members. The mean duration of last dose of vaccine to symptom onset was 45.9 ± 40.6 days in HCW and 60.7 ± 66.6 days in the family members. The proportion of different types of vaccine received by HCW were Covaxin 88%, Sinopharm 70%, Covishield 34% and Sputink V 30% whereas the proportion in their family members were Covaxin 27%, Sinopharm 68%, Covishield 56% and Sputink V 13%. Comorbid status was noted in 15% of HCW and 45% of family members. The prevalence of breakthrough hospitalization was 3 (3.1) HCW and 8 (6.4%) family members. The survival rate was 100% in HCW and 97% in family members. Non survivors were over 65 years and they had multiple comorbidities. Half of them received only 2 doses of vaccine; one was unvaccinated. Conclusions: The majority of cases with BTI in fourth wave was mild. The prevalence of breakthrough hospitalization was 3-6% in HCW and family members; showing the protective effect of vaccine from severe manifestation. Non-survivors were elderly, having multiple comorbidities and incomplete vaccination or unvaccinated. The chance of BTI was decreasing if they obtained 4 doses compared to 3 doses. The possibility of BTI after taking 3 doses of vaccine was 50% in HCW and 33% in family members; it dropped to 36% and 22% respectively after 4 doses of vaccine. Therefore, 3 doses of COVID-19 vaccine could protect 50-67 percent; the protective efficacy increased to 65-87 percent with 4 doses. Therefore, 4 doses of COVID-19 vaccine are recommended for prevention of fifth wave in Myanmar.