Objective: Establish and validate an experimental pain model that will create pain for at least 20-minutes and then use the model to determine if: 1) cryotherapy decreases experimentally induced pain, 2) experimentally induced pain contributes to arthrogenic muscle inhibition, and 3) cold application influences pain or arthrogenic muscle inhibition. To answer these questions we conducted two experiments, the results of which are presented in two manuscripts. Methods: Seventy (n = 30 for experiment I and n = 40 for experiment II), physically active healthy male subjects participated. Interventions: Independent variables used for experiment I were condition (5% hypertonic saline infusion/cryotherapy, no-saline infusion/cryotherapy, 5% hypertonic saline infusion/sham) and time (precondition, every minute during a condition, and 10 minutes following each condition). For experiment II, independent variables were treatment (saline infusion, saline infusion/cryotherapy, saline infusion/sham, and no-saline infusion) and time (pretreatment, posttreatment, and 30-minutes posttreatment). Dependent variables measured were pain perception, knee surface and ambient temperatures, and Hmax, and Mmax measures (experiment II only). Results: Saline caused more pain than no-saline at minutes 3, 4, and 5 during infusion. Pain caused by saline and sham application remained constant from 4 minutes during application through 1 minute following application. Cold application decreased pain for 16 minutes. Pain resulted in arthrogenic muscle inhibition following and 30 minutes following saline infusion. Cryotherapy removed inhibition following but not 30 minutes following application. Pain for the saline groups increased following infusion as measured with the pain rating index and visual analogue scale. According to pain rating index, cryotherapy did not decrease pain; however, cryotherapy decreased pain as measured with the visual analogue scales. No change in temperature occurred during the non-cooling conditions. Ambient temperatures fluctuated less than 1°C. Conclusion: Saline infusion caused anterior knee pain for over 20 minutes and resulted in arthrogenic muscle inhibition. Cryotherapy disinhibited the quadriceps motoneuron pool and reduced pain as measured with visual analogue scales. Cryotherapy did not decrease pain as measured with the McGill pain questionnaire.