The perception of pain and ability to cope with it varies widely amongst people, which in part could be due to the presence of inhibitory (antinociceptive) or facilitatory (pronociceptive) effects in conditioned pain modulation (CPM). This study examined whether individual differences in CPM reflect functional connectivity (FC) strengths within nodes of the descending antinociceptive pathway (DAP). A heat-based CPM paradigm and resting-state functional magnetic resonance imaging (rs-fMRI) were used to test the hypothesis that an individual's capacity to exhibit inhibitory CPM (changes in test stimuli [TS] pain due to a conditioning stimulus [CS]) reflects FC of the subgenual anterior cingulate cortex (sgACC), periaqueductal gray (PAG), and rostral ventromedial medulla (RVM). A total of 151 healthy participants (72 men, 79 women) underwent CPM testing and rs-fMRI. Three types of CPM were identified based on the effect of the CS on TS pain: (1) Antinociception: CS reduced TS pain in 45% of participants, (2) No-CPM: CS did not change TS pain in 15% of participants, and (3) Pronociception: CS increased TS pain in 40% of participants. Only the Antinociceptive subgroup exhibited FC between the left sgACC and PAG, right sgACC and PAG, and RVM and PAG. Furthermore, only the Antinociceptive subgroup exhibited a correlation of both left and right sgACC-RVM FC (medium effect sizes) with CPM effect magnitude. Women, compared with men were more likely to be categorized as pronociceptive. These data support the proposition that FC of the DAP reflects or contributes to inhibitory CPM.