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Simple Summary: The influence of different exposome factors on squamous cell carcinoma has been studied in several articles, although generally including a limited number of factors, especially chronic sun exposure. We carried out a prospective multicenter case–control study of patients with a history of squamous cell carcinoma and a control group with no previous history of skin cancer, in which we compared most of the exposome variables, including sun exposure, photoprotection habits, diet, pollution, stress, and lifestyle. We found a significant association between squamous cell carcinoma and multiple exposome-related factors besides chronic sun exposure in the Spanish population. A better understanding of the actual impact of exposome in this condition could help design primary prevention strategies targeted at specific populations or risk behaviors. Introduction: The concept of exposome refers to the total of harmful and beneficial environmental exposures that can help predict the organism's biological responses over time. Ultraviolet radiation (UVR) from sun exposure has been recognized as the main etiological agent of skin cancer, and squamous cell carcinoma (SCC) is one most commonly associated with chronic exposure. However, in recent years, evidence suggests that lifestyle, environmental pollution, and contaminants in water and food can have an influence. Objectives: To study the relationship between SCC and sun exposure, pollution, stress, and lifestyle in a Spanish cohort. Materials and Method: A multicenter case–control study was carried out in which 13 dermatologists from different regions of Spain recruited cases and controls between April 2020 and August 2022. The group of cases were patients diagnosed with SCC and, as a control group, people who attended Dermatology consultations as companions with no history of skin cancer. Results: A total of 62 patients with SCC and 126 controls were included (62.9% males, median age 76.46 (10.1) and 33.3%, median age 55.7 (15), respectively). The SCC group had experienced more outside work than the controls (75% vs. 22.4%, p < 0.001), less recreational exposure (sunbathing, p = 0.05, and outdoor sports, p = 0.01), and a lower annual income (p = 0.01), with an increase in tobacco exposure (p < 0.001), without differences in other carcinogens, such as ionizing radiation or chemical exposure. The control group had a higher daily screentime use (p < 0.001) and practiced more relaxation activities (p = 0.03). A higher linolenic acid intake and lower coffee consumption were the only dietary variables associated with SCC (p < 0.05). Some chronic medications (anxiolytics, antidepressants, beta-blockers, statins, hydrochlorothiazide, ACE inhibitors, metformin, and omeprazole) were also statistically associated with SCC. Statistical significance for all aforementioned variables was maintained in the multivariate analysis (p < 0.05). Conclusions: The study found a significant association between SCC and multiple exposome-related factors in addition to chronic sun exposure in the Spanish population. Primary prevention strategies should target specific populations, such as outdoor workers promoting sun-safe behaviors and stress-reducing activities, in addition to adequate skin photoprotection in patients under certain medications associated with SCC. [ABSTRACT FROM AUTHOR]