This review delves into the effects of autoimmune conditions like rheumatoid arthritis, inflammatory disorders such as irritable bowel syndrome, cardiovascular disease, diabetes, infectious ailments like human immunodeficiency virus, and their medications on periodontal therapy outcomes. It also explores the influence of hormones. Understanding these systemic factors is crucial for optimizing periodontal health and treatment efficacy. The review underscores the necessity of considering these variables in periodontal care. Other vital systemic factors are addressed elsewhere in this special edition.