- Background Ischemic stroke (IS) is a multifactorial disorder, a leading cause of long-term disability, and the second most common cause of death. Previous studies have examined the association between stroke and weather conditions with conflicting results. In this study we aimed to investigate the association between changes in ambient temperature and risk of IS onset. Methods We used a time-stratified case-crossover study design including all patients admitted to Soroka University Medical Center in southern Israel between 2012 and 2014 for IS. Exposure windows of 6, 12, 24, 48, 72, and 96 hours were examined. All patients were assessed and classified by a neurologist. Temperature (°C), and relative humidity (%) were obtained from monitoring stations located in Beer-Sheva. Results A total of 1,174 patients visited Soroka University Medical Center for admission for an IS during the study period. Among them, 56% were male, on average 69.8 ± 13.1 years old. IS incidence was associated with increase in temperature during the summer and autumn season over the 96 hours preceding symptoms onset; the odds ratio (OR) for an increase of 5°C was 3.10 (95% CI, 1.45–6.61) during the summer and 1.86 (95% CI, 1.15–2.99) in autumn. The association between temperature and stroke onset during the winter was negative (OR, 0.68; 95% CI, 0.48–0.97) for 96-hour moving average temperature exposure. Men were more sensitive to 96-hour exposure window temperature fluctuations (OR, 1.35; 95% CI, 1.01–1.80) than women (OR, 0.96; 95% CI, 0.68–1.36). We did not find any associations between IS onset and differences between the maximum and minimum measurements of temperature. Conclusions Our findings showed that short-term exposure to high temperatures is associated with a higher risk of IS in men but not in women. Further study is needed to validate this observation and to understand its pathophysiology.