A better knowledge of the burden and risk factors associated with severity due to spider bites would lead to improved management with a reduction of sequelae usually seen for this neglected health problem, and would ensure proper use of antivenoms in remote localities in the Brazilian Amazon. The aim of this study was to analyze the profile of spider bites reported in the state of Amazonas in the Western Brazilian Amazon, and to investigate potential risk factors associated with severity of envenomation. Methodology/Principal Findings We used a case-control study in order to identify factors associated with spider bite severity in the Western Brazilian Amazon from 2007 to 2014. Patients evolving to any severity criteria were considered cases and those with non-severe bites were included in the control group. All variables were retrieved from the official Brazilian reporting systems. Socioeconomical and environmental components were also included in a multivariable analysis in order to identify ecological determinants of incidence and severity. A total of 1,181 spider bites were recorded, resulting in an incidence of 4 cases per 100,000 person/year. Most of the spider bites occurred in males (65.8%). Bites mostly occurred in rural areas (59.5%). The most affected age group was between 16 and 45 years old (50.9%). A proportion of 39.7% of the bites were related to work activities. Antivenom was prescribed to 39% of the patients. Envenomings recorded from urban areas [Odds ratio (OR) = 0.40 (95%CI = 0.30–0.71; p<0.001)] and living in a municipality with a mean health system performance index (MHSPI >median [OR = 0.64 (95%CI = 0.39–0.75; p<0.001)] were independently associated with decreased risk of severity. Work related accidents [OR = 2.09 (95%CI = 1.49–2.94; p<0.001)], Indigenous status [OR = 2.15 (95%CI = 1.19–3.86; p = 0.011)] and living in a municipality located >300 km away from the state capital Manaus [OR = 1.90 (95%CI = 1.28–2.40; p<0.001)] were independently associated with a risk of severity. Living in a municipality located >300 km away from the state capital Manaus [OR = 1.53 (95%CI = 1.15–2.02; p = 0.003)] and living in a municipality with a MHSPI 300 km away from the state capital Manaus could be contributing factors to higher severity of spider envenomings in this area, as well as to antivenom underdosage