Patient safety is a high priority for the healthcare system worldwide. It is considered an indicator of the quality of care in any hospital building. This research assesses challenges in escape route designs in high-rise hospital buildings in Tanzania. Data were collected using the established questionnaire. The study population was 184 participants from five hospitals in Tanzania namely Muhimbili National Hospital, Agha khan Hospital, Kairuki Hospital, Rabinsia Hospital, and Temeke Hospital. Data were analyzed with Descriptive statistics and Principle component Analysis using SPSS. All of the ten domains of escape routes such as the presence of exit routes, enough staircases, and stairwells, clear directions to exit routes, presence of blockage in exit routes, locked exits, exit routes familiarity, presence of photo luminescent signs, presence of wide exit, visible exit signs and presence of smoke in stairways were established from theoretical knowledge to determine the challenges facing escape routes in high rise hospital buildings. Using the SPSS, the factor analysis through Principal Component Analysis (PCA) was conducted to determine the lesser number of factors or components which establish a dimension solution for the research. Bartlett's Test of Sphericity values shows that the variables are significantly correlated since the p-value is less than 0.05. Several factors with an Eigenvalue large than on (e>1), having four components solution model which explained the total variance of 58.24% were retained. Three variables namely the absence of wide exits, few staircases and stairwells, and stairways with smoke scored a high score of variance which indicate to have maximum effects on high-rise hospital buildings. Therefore, it is strongly recommended to maximize the size of exits, increase the number of staircases and stairwells, and other vertical circulation, and ensure exits are protected from smoke for effective escape routes performance.