Epidemiological evidence indicates that nearly 100,000 Gulf War veterans (GWVs) returned from the Persian Gulf reporting myriad symptoms with no apparent medical explanation. Predictive and confirmatory factor analytic procedures verified musculoskeletal pain as one of three categories describing the unexplained symptoms of GWVs. Over a decade has passed and the pain complaints of GWVs have received little scientific attention, beyond establishing that a problem exists. PURPOSE To comprehensively assess pain sensitivity and to determine the effect of exercise in GWVs with medically unexplained musculoskeletal pain versus healthy veteran controls. METHODS Thirty GWVs (n=12 unexplained muscle pain; n=18 healthy) completed a series of psychophysical pain assessments designed to determine pain sensitivity to heat and pressure stimuli. Testing included: 1) measures of pressure pain threshold and tolerance (in seconds), 2) suprathreshold ratings for pressure pain intensity and affect (0–20 scale), 3) heat pain thresholds (degrees C), and 4) pain intensity and affect ratings in response to temperatures ranging from 44 degrees C to 50 degrees C (Descriptor Differential Scaling). Testing occurred prior to and following 30 minutes of cycling exercise set at 70% of peak oxygen capacity. RESULTS There were no group differences in age, height, weight or self-reported physical activity. There were no group differences for either pressure or heat pain thresholds or pressure pain ratings. GWVs with unexplained muscle pain consistently rated heat stimuli as more intense and unpleasant compared to controls both pre [Intensity: F(1,27)=4.1, p=0.05; Affect: F(1,27)=5.4, p=0.03] and post [Intensity: F(1,27)=7.9, p=0.009; Affect: F(1,27)=7.4, p=0.01] exercise. GWVs with unexplained pain rated exercise as more painful (t=3.2, p=0.003), but not as requiring more effort than controls. Exercise generally had a large effect on heat pain ratings for sick veterans but had no effect on heat pain ratings for healthy veteran controls. CONCLUSIONS GWVs with medically unexplained musculoskeletal pain are more sensitive to experimental heat pain stimuli than healthy veteran controls, with the differences being larger following 30 minutes of intense exercise. Surprisingly, healthy GWVs did not exhibit the expected analgesic response following exercise. Our data suggest that a multidimensional and multimodal approach are important for determination of psychophysical differences and exercise effects in GWVs with medically unexplained musculoskeletal pain. Supported by DVA #561-00215