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Hand, foot, and mouth disease (HFMD) is an enterovirus-mediated condition that predominantly affects children under 5 years of age. The tendency for outbreaks to peak in warmer summer months suggests a relationship between HFMD and weather patterns. We reviewed the English-language literature for articles describing a relationship between meteorological variables and HFMD. Seventy-two studies meeting criteria were identified. A positive, statistically significant relationship was identified between HFMD cases and both temperature (61 of 67 studies, or 91.0%, reported a positive relationship) [CI 81.8-95.8%, P = 0.0001] and relative humidity (41 of 54 studies, or 75.9%) [CI 63.1-85.4%, P = 0.0001]. No significant relationship was identified between HFMD and precipitation, wind speed, and/or sunshine. Most countries reported a single peak of disease each year (most commonly early Summer), but subtropical and tropical climate zones were significantly more likely to experience a bimodal distribution of cases throughout the year (two peaks a year; most commonly late spring/early summer, with a smaller peak in autumn). The rising global incidence of HFMD, particularly in Pacific Asia, may be related to climate change. Weather forecasting might be used effectively in the future to indicate the risk of HFMD outbreaks and the need for targeted public health interventions.