Article Info Background: Musculoskeletal disorders (MSDs) are one of the most common work-related illnesses, which lead to high costs and a reduction in labor productivity. The aim of this study was to investigate the relationship between MSDs with mental workload (MWL) and occupational fatigue among the office staff of a communication service in Tehran, Iran, in 2017. Materials and Methods: This descriptive study was conducted on 94 staff of a communication service company in June 2017. The data collection tools included Rapid Office Strain Assessment (ROSA), NASA Task Load Index (NASA-TLX) questionnaire and Swedish Occupational Fatigue Inventory (SOFI). Data analysis conducted using descriptive statistics and one-way ANOVA test in SPSS software. Results: 73% of the participants were women with mean age of 28.25 ± 3.40 years and the remaining participants were men with mean age of 26.91 ± 4.60 years. According to the results of the Nordic questionnaire, the highest pain was observed in the neck (65.94%) during the last year. According to the results of the ROSA, 71% of the participants were at the warning risk level and the need for ergonomic interventions. In addition, the relationship between occupational fatigue and its subscales with MSDs was significant in all cases (P < 0.001). Finally According to the results, the participants' MWL was high. Conclusions: The results of the present study showed that high workload and occupational fatigue cause MSDs, and intervention is necessary in these individuals.