Introduction: Musculoskeletal dysplasias (MSD) are inherited conditions of abnormal cartilage and bone development and remodeling which include, amongst others, multiple epiphyseal dysplasia (MED), spondyloepiphyseal dysplasia (SED), achondroplasia, and hypochondroplasia. The aim of this study was to compare patient characteristics and in-hospital complications between MSD and non-MSD patients undergoing total joint arthroplasty (TJA). Hypothesis: MSD patients undergoing TJA are at increased risk of in-hospital post-operative complications and mortality compared to non-MSD patients. Materials and methods: The Nationwide Inpatient Sample (NIS) from the years 2005 to 2014 was used for this retrospective cohort study. International Classification of Diseases, Clinical Modifications (ICD-9-CM) procedure codes identified primary total knee arthroplasty (TKA) and total hip arthroplasty (THA) procedures and were used to separate MSD and non-MSD patients. Patients with trauma or malignancy as primary diagnoses, non-elective procedures, revision procedures, and concurrent bilateral surgeries were excluded. Patients were compared using linear regression or multivariate logistic regression analysis to control for confounders. All statistical analyses were performed taking into account the NIS sampling scheme and associated sampling weights. Results: A total of 1,255 patients comprised the MSD group and 8,027,181 patients the non-MSD group. MSD patients were younger than non-MSD patients (50.9 vs. 65.8 years, p < 0.001), with less comorbidities including: hypertension (40.2% vs. 64.5%, p < 0.001), coronary artery disease (5.5% vs. 12.9%, p < 0.001), diabetes mellitus (9.4% vs. 19.0%, p < 0.001), and hypothyroidism (7.8% vs. 14.7%, p = 0.002). MSD patients had higher risks of surgical site infection (0.8% vs. 0.2%; OR, 4.16; 95% CI, 1.03–16.75; p = 0.044), and perioperative hemorrhage (2.1% vs. 0.7%; OR, 3.20; 95% CI, 1.32–7.76; p = 0.010). Discussion: MSD patients undergoing TJA were younger with less co-morbidity compared to non-MSD patients, and had no significant difference in overall perioperative medical and surgical complication rates. However, they are at increased risk for surgical site infection and perioperative hemorrhage possibly due to the anatomical complexity encountered. Level of Evidence: III, Retrospective Cohort.